Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists

ABSTRACT

Compounds of formula (I) wherein X is (a) or (b), R is Het as defined in the description. These compounds are oxytocin and vasopressin antagonists useful in the treatment of preterm labor, dysmenorrhea, and for the stoppage of labor preparatory to Cesarean delivery. ##STR1##

FIELD OF THE INVENTION

This application is a 371 of PCT/US 93/12565, filed Dec. 23, 1993 whichis a continuation-in-part of application Ser. No. 07/993,861, filed Dec.23, 1992 now abandoned, which is a continuation-in-part of applicationSer. No. 07/760,416, filed Sep. 16, 1991, now abandoned.

The present invention provides novel compounds, novel compositions,methods of their use and methods of their manufacture, such compoundsgenerally pharmacologically useful as agents in obstetric andgynecologic therapy. The aforementioned pharmacologic activities areuseful in the treatment of mammals. More specifically, the compounds ofthe present invention can be used in the treatment of preterm labor,stopping labor preparatory to Cesarean delivery, and in the treatment ofdysmenorrhea. At the present time, there is a need in the area ofobstetric and gynecologic therapy for such agents.

BACKGROUND OF THE INVENTION

In the field of obstetrics, one of the most important problems is themanagement of preterm labor. A significant number of the pregnanciesprogressing past 20 weeks of gestation experience premature labor anddelivery, which is a leading cause of neonatal morbidity and mortality.Despite major advances in neonatal care, retention of the fetus in uterois preferred in most instances.

Tocolytic (uterine-relaxing) agents that are currently in use include β₂-adrenergic agonists, magnesium sulfate and ethanol. Ritodrine, theleading β₂ -adrenergic agonist, causes a number of cardiovascular andmetabolic side effects in the mother, including tachycardia, increasedrenin secretion, hyperglycemia (and reactive hypoglycemia in theinfant). Other β₂ -adrenergic agonists, including terbutaline andalbuterol have side effects similar to those of ritodrine. Magnesiumsulfate at plasma concentrations above the therapeutic range of 4 to 8mg/dL can cause inhibition of cardiac conduction and neuromusculartransmission, respiratory depression and cardiac arrest, thus makingthis agent unsuitable when renal function is impaired. Ethanol is aseffective as ritodrine in preventing premature labor, but it does notproduce a corresponding reduction in the incidence of fetal respiratorydistress that administration of ritodrine does.

It has been proposed that a selective oxytocin antagonist would be theideal tocolytic agent. In the last few years, evidence has accumulatedto strongly suggest that the hormone oxytocin is the physiologicalinitiator of labor in several mammalian species including humans.Oxytocin is believed to exert this effect in part by directlycontracting the uterine myometrium and in part by enhancing thesynthesis and release of contractile prostaglandins from the uterineendometrium/decidua. These prostaglandins may, in addition, be importantin the cervical ripening process. By these mechanisms, the process oflabor (term and preterm) is initiated by a heightened sensitivity of theuterus to oxytocin, resulting in part as a result of a well-documentedincrease in the number of oxytocin receptors in this tissue. This"up-regulation" of oxytocin receptors and enhanced uterine sensitivityappears to be due to trophic effects of rising plasma levels of estrogentowards term. By blocking oxytocin, one would block both the direct(contractile) and indirect (enhanced prostaglandin synthesis) effects ofoxytocin on the uterus. A selective oxytocin blocker, or antagonist,would likely be more efficacious for treating preterm labor than currentregimens. In addition, since oxytocin at term has major effects only onthe uterus, such an oxytocin antagonizing compound would be expected tohave few, if any, side effects.

The compounds of the present invention can also be useful in thetreatment of dysmenorrhea. This condition is characterized by cyclicpain associated with menses during ovulatory cycles. The pain is thoughtto result from uterine contractions and ischemia, probably mediated bythe effect of prostaglandins produced in the secretory endometrium. Byblocking both the direct and indirect effects of oxytocin on the uterus,a selective oxytocin antagonist can be more efficacious for treatingdysmenorrhea then current regimens.

It is, therefore, a purpose of this invention to provide substanceswhich more effectively antagonize the function of oxytocin in diseasestates in animals, preferably mammals, especially in humans. It isanother purpose of this invention to prepare novel compounds which moreselectively inhibit oxytocin. It is still another purpose of thisinvention to provide a method of antagonizing the functions of oxytocinwhen oxytocin activity is responsible for causing disease states inmammals. It is also a purpose of this invention to develop a method ofpreventing or treating oxytocin-related disorders of preterm labor anddysmenorrhea by antagonizing oxytocin.

It has now been found that compounds of the present invention areantagonists of oxytocin and bind to the oxytocin receptor. When theoxytocin receptor is bound by the compounds of the present invention,oxytocin is antagonized by being blocked from its receptor and thusbeing unable to exert its biologic or pharmacologic effects. Thesecompounds are useful in the treatment and prevention of oxytocin-relateddisorders of animals, preferably mammals and especially humans. Thesedisorders are primarily preterm labor and dysmenorrhea. The compoundswould also find usefulness for stoppage of labor preparatory to Cesareandelivery.

SUMMARY OF THE INVENTION

The compounds of the present invention and their pharmaceuticallyacceptable salts and esters are those of the general structural formula:##STR2## wherein X is ##STR3## a is a single or double bond, R is Het,wherein

Het is a substituted saturated or unsaturated heterocyclic ring whereinsaid substituents are independently one or more of R¹, R², R³, Alk-R¹,Alk-R², Alk-R³, --NHC(O)--Alk-R² R³, --NR⁵ --Alk-R² R³ or Alk-R² R³ ;where Alk is C₁₋₁₀ alkyl and R¹, R² and R³ are independently selectedfrom the group consisting of hydrogen, halogen, C₂₋₁₀ alkenyl,methylene, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkylamino,C₁₋₁₀ alkoxycarbonylamino, C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl,C₁₋₁₀ alkylcarbonylamino, --S--R⁴, C₁₋₁₀ alkylcarbonyloxy, C₁₋₁₀alkylsulfonyl, C₁₋₁₀ alkylthio, amino, amino C₁₋₁₀ alkylcarbonylamino,amino C₁₋₁₀ alkylamino, carbonylamino, carbamoyl, carboxyl C₁₋₁₀alkylamino, carboxyl, cyano, di-C₁₋₁₀ alkylamino, di-C₁₋₁₀alkylamino-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylthio,di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl, guanidinyl, hydroxyl,hydroxyl C₁₋₁₀ alkylamino, imidazolyl, imidazolyl amino, imidazolylC₁₋₁₀ alkylamino, imidazolyl C₁₋₁₀ alkylaminocarbonyl, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl,piperidinylamino, piperazinyl, pyrrolidinyl, sulfonyl, tetrazolyl C₁₋₁₀alkylcarbonylamino, tetrazolylaminocarbonyl, phosphoryl, phosphorylC₁₋₁₀ alkylamino and thiono;

R⁴ is selected from the group consisting of imidazolyl, C₁₋₁₀alkoxycarbonyl-C₁₋₁₀ alkyl, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkyl and C₁₋₅alkyl; and

R⁵ is selected from the group consisting of hydrogen and C₁₋₅ alkyl.

In one embodiment of the instant invention are compounds represented bythe formula ##STR4## wherein X is ##STR5## a is a single or double bond,R is Het, wherein

Het is a mono, di, tri or tetra substituted saturated or unsaturated 5or 6 membered heterocyclic or 7 to 10 membered heterobicyclic ringcontaining 1, 2 or 3 nitrogen atoms, wherein said substituents areindependently one or more of R¹, R², R³, Alk-R¹, Alk-R², Alk-R³,--NHC(O)--Alk--R² R³, --NR⁵ --Alk--R² R³ or Alk--R² R³ ; where Alk isC₁₋₁₀ alkyl and R¹, R² and R³ are independently selected from the groupconsisting of hydrogen, halogen, C₂₋₁₀ alkenyl, methylene, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkylamino, C₁₋₁₀alkylcarbonylamino, C₁₋₁₀ alkylsulfonyl, --S--R⁴, amino, amino-C₁₋₁₀alkylcarbonylamino, amino C₁₋₁₀ alkylamino, carbamoyl, carboxyl C₁₋₁₀alkylamino, carboxyl, cyano, di-C₁₋₁₀ alkylamino, di-C₁₋₁₀alkylamino-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylthio,di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl, guanidinyl, hydroxyl,hydroxyl-C₁₋₁₀ alkylamino, imidazolyl, imidazolyl amino,imidazolyl-C₁₋₁₀ alkylamino, morpholinyl, thiomorpholinyl,dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino,piperazinyl, sulfonyl, phosphoryl, phosphoryl C₁₋₁₀ alkylamino andthiono;

R⁴ is selected from the group consisting of imidazolyl, C₁₋₁₀alkoxycarbonyl-C₁₋₁₀ alkyl, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkyl and C₁₋₅alkyl; and

R⁵ is selected from the group consisting of hydrogen and C₁₋₅ alkyl.

In a second embodiment of the instant invention are compoundsrepresented by the formula ##STR6## or a pharmaceutically acceptablesalt thereof, wherein a is a single or double bond,

R is Het, wherein

Het is a mono, di, tri or tetra substituted saturated or unsaturated 5or 6 membered heterocyclic ring containing 1, or 2 nitrogen atoms thatis bonded to said bicyclic ring at one of said heterocyclic ring'snitrogen atoms, wherein said substituents are independently one or moreof R¹, R², R³, Alk-R¹, Alk-R², Alk-R³ or Alk-R² R³ ; and where Alk isC₁₋₁₀ alkyl and R¹, R² and R³ are independently selected from the groupconsisting of hydrogen, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀alkoxycarbonyl-C₁₋₁₀ alkylamino, C₁₋₁₀ alkoxycarbonylamino, C₁₋₁₀alkylamino-C₁₋₁₀ alkylaminocarbonyl, C₁₋₁₀ alkylcarbonylamino, C₁₋₁₀alkylcarbonyloxy, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ alkylthio, amino,amino-C₁₋₁₀ alkylcarbonylamino, carbonylamino, carboxyl C₁₋₁₀alkylamino, carboxyl, carboxyl C₁₋₁₀ alkylamino, cyano, di-C₁₋₁₀alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl, guanidinyl,hydroxyl, imidazolyl, imidazolyl C₁₋₁₀ alkylaminocarbonyl, indolyl, oxo,phenyl, piperidinylamino, piperizinyl, pyrrolidinyl, sulfonyl,tetrazolyl-C₁₋₁₀ alkylcarbonylamino, tetrazolylaminocarbonyl and thiono.

Salts encompassed within the term "pharmaceutically acceptable salts"refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid. Representative salts include the following salts:

    ______________________________________                                        Acetate            Lactobionate                                               Benzenesulfonate   Laurate                                                    Benzoate           Malate                                                     Bicarbonate        Maleate                                                    Bisulfate          Mandelate                                                  Bitartrate         Mesylate                                                   Borate             Methylbromide                                              Bromide            Methylnitrate                                              Calcium Edetate    Methylsulfate                                              Camsylate          Mucate                                                     Carbonate          Napsylate                                                  Chloride           Nitrate                                                    Clavulanate        N-methylglucamine                                          Citrate            Oxalate                                                    Dihydrochloride    Pamoate (Embonate)                                         Edetate            Palmitate                                                  Edisylate          Pantothenate                                               Estolate           Phosphate/diphosphate                                      Esylate            Polygalacturonate                                          Fumarate           Salicylate                                                 Gluceptate         Stearate                                                   Gluconate          Subacetate                                                 Glutamate          Succinate                                                  Glycollylarsanilate                                                                              Tannate                                                    Hexylresorcinate   Tartrate                                                   Hydrabamine        Teoclate                                                   Hydrobromide       Tosylate                                                   Hydrocloride       Triethiodide                                               Hydroxynaphthoate  Valerate                                                   Iodide                                                                        Isethionate                                                                   Lactate                                                                       ______________________________________                                    

The term "pharmacologically effective amount" shall mean that amount ofa drug or pharmaceutical agent that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by a researcher or clinician.

The term "alkyl" shall mean straight or branched chain alkanes of one toten total carbon atoms or any number within this range.

The term "alkenyl" shall mean straight or branched chain alkenes, withone or more degrees of unsaturation at any position on the chain, of twoto ten total carbon atoms, or any number within this range.

The term "aryl" shall mean phenyl.

The term "cycloalkyl" shall mean cyclic rings of alkanes, alkenes oralkynes with one or more degrees of unsaturation at any position of thering, of three to eight total carbon atoms.

Whenever the terms "alkyl" or "aryl" or either of their prefix rootsappear in a name of a substituent (e.g., aralkoxyaryloxy) they shall beinterpreted as including those limitations given above for "alkyl" and"aryl". Designated numbers of carbon atoms (e.g., C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The term "heterocyclic" or "heterocycle," as used herein except wherenoted, represents a stable mono, di, tri or tetra-substituted 5- to7-membered mono- or bicyclic or stable mono, di, tri ortetra-substituted 7- to 10-membered bicyclic heterocyclic ring systemany ring of which may be saturated or unsaturated, and which consists ofcarbon atoms and from one to three heteroatoms selected from the groupconsisting of N and O. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic elements include piperidinyl,piperazinyl, azepinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, 4-piperidonyl, imidizolyl, imidazolinyl,imidazolidinyl, triazolyl, triazolinyl, triazolidinyl, morpholinyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isoxazolyl, isoxazolidinyl, quinuclidinyl, indolyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, oxadiazolyl,triazaspirodecane, pyrrolo-isoxazole, pyrrolo-pyrazole, andpyrrolo-pyrrole.

The term "oxo" shall refer to the substituent ═O.

The term "thiono" shall refer to the substituent ═S.

The term "phosphoryl" shall refer to the substitutent --OPO(OH)₂.

The term "oxiranyl" shall refer to the substituent ##STR7##

The term "dioxothiomorpholinyl" shall refer to the

substituent ##STR8##

The term "halogen" shall include iodine, bromine, chlorine and fluorine.

The term "preterm labor" shall mean expulsion from the uterus of aviable infant before the normal end of gestation, or more particularly,onset of labor with effacement and dilation of the cervix before the37th week of gestation. It may or may not be associated with vaginalbleeding or rupture of the membranes.

The term "dysmenorrhea" shall mean painful menstruation.

The term "cesarean delivery" shall mean incision through the abdominaland uterine walls for delivery of a fetus.

The term "substituted" shall be deemed to include multiple degrees ofsubstitution by a named substitutent.

The ability of the compounds of the present invention to antagonizeoxytocin makes these compounds useful as pharmacologic agents formammals, especially for humans, for the treatment and prevention ofdisorders wherein oxytocin may be involved. Examples of such disordersinclude preterm labor and especially dysmenorrhea. These compounds mayalso find usefulness for stoppage of labor preparatory to Cesareandelivery.

Because of the known relationship of vasopressin to oxytocin, thecompounds of the present invention are also useful as vasopressinantagonists. Vasopressin antagonists are useful in the treatment orprevention of disease states involving vasopressin disorders, includingtheir use as diuretics and their use in congestive heart failure.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each including timed release andsustained release formulations), pills, powders, granules, elixers,tinctures, suspensions, syrups and emulsions. Likewise, they may also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseof ordinary skill in the pharmaceutical arts. An effective but non-toxicamount of the compound desired can be employed as a tocolytic agent.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.3-6.0 gm/day orally. Intravenously,the most preferred doses will range from 0.1 to about 10 mg/minuteduring a constant rate infusion. Advantageously, compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred compounds for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin that art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittant throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as "carrier" materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carders to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The compounds of the present invention can be prepared readily accordingto the following reaction Schemes (in which all variables are as definedbefore) and Examples or modifications thereof using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants which arethemselves known to those of ordinary skill in this art, but are notmentioned in greater detail.

The most preferred compounds of the invention are any or all of thosespecifically set forth in these examples. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise.

Abbreviations used in the Examples are as follows:

TEA=triethylamine

DIEA=diisopropylethylamine

BOP=benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate

THF=tetrahydrofuran

DMF=dimethylformamide

LAH=lithium aluminum hydride

TFA=trifluoroacetic acid

HPLC Method A =15 min. linear gradient 95:5 A:B to 0:100 A:B

A=H₂ O containing 0.1% by vol. TFA

B=CH₃ CN containing 0.1% by vol. TFA

2.0 mL/min flow rate

12 cm C₁₈ reverse phase column

UV detection (215 nm)

HPLC Method B=20 min. linear gradient 90:10 A:B to 5:95 A:B

A=H₂ O containing 0.1% by vol. phosphoric acid

B=CH₃ CN containing 0.1% by vol. phosphoric acid

2.0 mL/min flow rate

12 cm C₁₈ reverse phase column

UV detection (215 nm)

TLC was performed on 20 cm plates coated with silica gel (250 microns)from Analtech.

EXAMPLE A

Endo-(1S)-1'(((2-amino-7,7-dimethylbicyclo(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1,4'-piperidine)##STR9##

Di-t-butyl dicarbonate (31 g, 0.14 mole available from Aldrich) andbis(2-chloroethyl) amine hydrochloride (21.6 g, 0.12 mole Aldrich) werecombined in CH₂ Cl₂ (250 ml) stirred at ambient temperature and treatedwith triethylamine (12.8 g, 0.127 mole) added dropwise over 15 minutes.After 1 hour, another 1.5 ml of triethylamine was added. After a totalof 2.5 hours, the mixture was poured onto a silica gel column packedwith CH₂ Cl₂ :hexane (1:1), and eluted with CH₂ Cl₂. The combinedproduct fractions were evaporated to dryness in vacuo to giveN,N-bis(2-chloroethyl)-t-butyl-carbamate.

To a solution of indene (10.3 g, 89 mmole) in dry tetrahydrofuran (THF,18 ml) cooled in an ice bath and maintained under a nitrogen blanket wasadded lithium bis(trimethylsilyl)amide (Aldrich, 177 ml of a 1.0Msolution in THF; 177 mmole) over 15 minutes. The mixture was stirred inthe cold for 30 minutes, then added over 15 minutes to a solution ofN,N-bis(2-chloroethyl)-t-butylcarbamate (21.2 g, 88 mmole) stirred in anice bath. The mixture was stirred for 2 hours in the cold and for 30minutes at ambient temperature under nitrogen, then evaporated in vacuoto a foam. CH₂ Cl₂ was added and the resulting mixture poured onto asilica gel column packed with 40% hexane in CH₂ Cl₂. The column waseluted with 40% hexane in CH₂ Cl₂ followed by CH₂ CL₂, and the productfractions were evaporated to dryness in vacuo to provide1'-(t-butyloxycarbonyl)-spiro(indene-1,4'-piperidine).

1'-(t-Butyloxycarbonyl)spiro(indene-1,4'-piperidine) (16 g, 56 mmole) inethyl acetate (250 ml) was stirred in an ice bath and saturated withHCl(g) for 30 minutes. The mixture was evaporated to dryness. Ethylacetate was added and removed in vacuo three times, and the residue wastriturated with diethyl ether and filtered to providespiro(1H-indene-1,4'-piperidine) hydrochloride. The free base wasobtained by slurrying the hydrochloride in aqueous sodium bicarbonatesolution and extracting with CH₂ Cl₂. The organic layer was separated,dried over sodium sulfate, filtered, and evaporated to dryness in vacuoto provide spiro(1H-indene-1,4'piperidine.

Spiro(1H-indene-1,4'piperidine) (308 mg, 1.66 mmol) and(+)-10-camphorsulfonyl chloride (418 mg, 1.66 mmol) were combined in CH₂Cl₂ and treated with triethylamine (0.23 ml). The mixture was stirred atambient temperature for 15 minutes, then poured onto a silica gel columnand eluted with 1:1 CH₂ Cl₂ :hexane. The product fractions were combinedand evaporated to dryness in vacuo to provide(1S)-1'-(((7,7-dimethyl-2-oxobicicylo-(2.2.1)hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine)as a solid which was recrystallized from petroleum ether and driedovernight in vacuo at ambient temperature.

(1S)-1'-(((7,7-dimethyl-2-oxobicyclo(2.2.1)hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (30 g, 0.075mole) in pyridine (500 mL) was heated in an oil bath to 70° C.(internal). Hydroxylamine hydrochloride (30 g) was added in threeportions over ca. 20 minutes. After 2 hours, an additional 10 g ofhydroxylamine hydrochloride was added (over 10 minutes). At 30, 40, and50 minutes additional elapsed time, further 3 g lots of hydroxylaminehydrochloride were added. After another 30 minutes, the mixture waspoured into water (2 L) and extracted 3 times with ethyl acetate (300 mLportions). The organic layers were combined, washed with 1N HCl (600 mLtotal), dried over sodium sulfate, filtered, and evaporated to drynessin vacuo. EtOH (abs; ca. 250 mL) was added to the resulting thick syrupand the solution allowed to stand at ambient temperature overnight. Themixture was filtered and the filtrate boiled down to ca. 80 mL. Afterstanding, the mixture was again filtered and boiled down to ca. 20 mL.After a third filtration, the filtered solids were combined to give(1S)-1'-(((7,7-dimethyl-2-oximinobicyclo(2.2.1)hept-1-yl)-methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (28 g).

Freshly prepared, activated Raney Nickel catalyst (ca. 30 g) in waterwas allowed to settle and the water decanted. Abs. ethanol (300 mL) wasadded, and the mixture swirled and again allowed to settle. The solventwas decanted. Two more wash-decant cycles with 150 mL of ethanol weresimilarly carried out. (1S)-1'-(((7,7-dimethyl-2-oximinobicyclo(2.2.1)hept-1-yl)methyl)sulfonyl)-spiro(1H-indene-1, 4'-piperidine) (30g) was stirred in a mixture of abs. ethanol (450 mL) and2-methoxyethanol (900 mL), nitrogen was bubbled through thesuspension/solution, and the Raney Nickel catalyst was added. Themixture was hydrogenated under 50 psi overnight. TLC (9:1 CH₂ C₂ MeOH,silica gel) showed the reaction to be complete. The catalyst was removedby filtration, and the filtrate evaporated to dryness in vacuo. Thecrude solid (27 g) was divided into 7 g batches, and each batch wasdissolved in methylene chloride (ca. 200 mL) and flash chromatographedon silica (700 g in a 100 mm column, packed and eluted with 8% (v/v)methanol in methylene chloride), taking 200 mL fractions. The exo isomerof the title amine was obtained in fractions ca. 5-7, and the desiredendo isomer in fractions ca. 8-16. TLC was on silica, eluted with 8%methanol-methylene chloride, phosphomolybdic acid stain. The combinedproduct fractions were evaporated to dryness to provide the titlecompound (4.5 g from each 7 g lot, ca. 18 g total) as a colorless solid.

EXAMPLE B

1-((7,7-Dimethyl-2-oxo-bicyclo(2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine##STR10##

To a stirred, 0° C. solution of 1-(o-tolyl)piperazine hydrochloride(50.0 g; 235 mmol) and TEA (83 mL; 590 mmol) in chloroform (1000 mL) wasadded (+)-10-camphorsulfonyl chloride (65.5 g; 260 mmol). The solutionwas stirred at 0° C. for 1 h and then at ambient temperature for 3 h.The solution was extracted with 5% aqueous HCl (2×500 mL), water (500mL), and saturated aqueous NaHCO₃ (2×500 mL). The organic phase wasdried (MgSO₄), filtered, and the solvent was removed under reducedpressure. The resulting solid was recrystallized from methanol to givethe title compound, mp 112°-114° C. (69 g; 75%).

Analysis calculated for (C₂₁ H₃₀ N₂ O₃ S) C, 64.57; H, 7.74; N, 7.17Found: C, 64.52; H, 7.68; N, 6.99

TLC: R_(f) 0.49 (75:25 hexane/ethyl acetate)

HPLC (method A): retention time 10.33 min

FAB MS: m/z 391 (M⁺ +H)

¹ H NMR (300 MHz, CDCl₃): δ7.2 (m, 2H), 7.0 (m, 2H), 3.45 (m, 4H), 3.40(d, J=16 Hz, 1H), 3.0 (m, 4H), 2.57 (m, 1H), 2.40 (dt, Jd=14 Hz, Jt=3Hz, 1H), 2.30 (s, 3H), 2.10 (m, 2H), 1.96 (d, J=14 Hz, 1H), 1.67 (m,1H), 1.44 (m, 1H), 1.18 (s, 3H), 0.91 (s, 3H)

EXAMPLE 1

(1S)-1'-(((7,7-dimethyl-2-endo-(4-nitrophenyloxycarbonylamino)-bicyclo-(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indane-1,4'-piperidine)

The product of Example A 3.47 mmol! and 4-nitrophenyl chloroformate 3.64mmol! were combined in THF. The reaction mixture was treated withtriethylamine 4.54 mmol! and allowed to stir for 2 hours. The reactionmixture was concentrated to dryness and the resulting residue waspurified by a silica gel column, while eluting with 1% ethyl acetate inmethylene chloride. The product fractions were combined and concentratedto dryness in vacuo. The title compound was obtained as a white solidfrom ether.

EXAMPLE 2 ##STR11##(1S)-1'-(((7,7-dimethyl-2-endo-(4-nitrophenyloxycarbonylamino)-bicyclo-(2.2.1)-hept-1-yl)-methyl))sulfonyl)spiro(1H-indane-1,4'-piperidine)1.80 mmol! and histidine methyl ester dihydrochloride 1.90 mmol! werecombined in DMF. The reaction mixture was treated with triethylamine5.90 mmol! and allowed to stir for 2 hours. The reaction mixture wasconcentrated to dryness and the resulting residue was dissolved in CH₂Cl₂. This CH₂ Cl₂ solution was placed on a silica gel column and elutedwith 2% methanol in CH₂ Cl₂ and then with 95/5/0.5 of CH₂ Cl₂/methanol/ammonium hydroxide. The product fractions were combined andevaporated to dryness in vacuo. A white solid was obtained from ether.The resulting white solid 0.954 mmol! and sodium hydride 0.45 mmol! werecombined in ethanol and left to stir for 12 hours. The reaction mixturewas concentrated to dryness and the resulting residue was dissolved inCH₂ Cl₂. This solution was placed on a silica gel column and eluted with95/5/0.5 of CH₂ Cl₂ /methanol/ammonium hydroxide. The product fractionswere combined and evaporated to dryness in vacuo. The title compound wasobtained as a white solid from ether and dried in vacuo, overnight.

m.p.: 146° C.-192° C.

NMR: Consistent with structure

HPLC: >99% pure

MS: M+H⁺ =566.2 (FAB)

CHN: Calc'd for C₃₀ H₃₉ N₅ O₄ S.0.05 C₄ H₁₀ O.0.80 H₂ O; C, 62.12; H,7.10; N, 12.00. Found: C, 62.10; H, 7.02; N, 12.01.

EXAMPLE 3 ##STR12##

The procedure of Example 2 was carried out using the product of Example1 0.197 mmol!, triethylamine 0.54 mmol! and substitutingglutamine-t-butyl ester hydrochloride 0.217 mmol! for histidinne methylester dihydrochloride. Chromatographic elution for column 1 was with 1%methanol in CH₂ Cl₂ and then with 3% methanol in CH₂ Cl₂. The titlecompound was obtained as a white solid from ether and dried in vacuo,overnight.

mp: 104°-166° C.

NMR: Consistent with structure

HPLE: >97% pure

MS: M+H⁺ =557.2 (FAB)

CHN: Calc'd for C₂₉ H₄₀ N₄ O₅ S.0.50 C₄ H₁₀ O.0.10 H₂₀ ; C, 62.51; H,7.65; N, 9.41. Found: C, 62.55; H, 7.36; N, 9.04.

EXAMPLE 4 ##STR13##

The procedure of Example 2 was carded out using the product of Example 10.215 mmol!, triethylamine 0.55 mmol! and substituting L-methioninemethyl ester 0.239 mmol! for histidine methyl ester dihydrochloride.Chromatographic elution for column 1 was with 96/4/0.4 of CH₂ Cl₂/methanol/ammonium hydroxide. For column 2, the elution was done with 5%methanol in CH₂ Cl₂ and then with 95/5/0.5 of CH₂ Cl₂ /methanol/ammoniumhydroxide. A white solid was obtained from ether. This white solid wasdissolved in methanol. This solution was treated with oxone 0.284 mmol!,which had been dissolved in a small amount of water, and the mixture wasstirred at ambient temperature for 4 hours. The reaction mixture wasconcentrated and the resulting residue was partitioned between ethylacetate and sat'd sodium bicarbonate solution. The ethyl acetate layerwas dried over sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by a silica gel column,eluted with 2% methanol in CH₂ Cl₂. The product fractions were combinedand concentrated. The title compound was obtained as a white solid fromether, and dried in vacuo, overnight.

m.p.: 134°-209° C.

NMR: Consistent with structure

HPLC: >97% pure

MS: M+H⁺ =592 (FAB)

CHN: Calc'd for C₂₉ H₄₁ N₃ O₆ S₂ ; C, 58.86; H, 6.98; N, 7.10. Found: C,58.55; H, 6.59; N, 7.04.

EXAMPLE 5 ##STR14##

The procedure of Example 2 was carried out using the product of Example1 0.366 mmol!, triethylamine 0.83 mmol!, and substitutingN-α-Cbz-L-Lysine methyl ester 0.379 mmol! for histidine methyl esterdihydrochloride. Chromatographic elution for column 1 was with 95/5/0.5of CH₂ Cl₂ /methanol/ammonium hydroxide. For column 2, the elution wasdone with 2% methanol in CH₂ Cl₂. A white solid was obtained from ether.This white solid was combined with palladium hydroxide on carboncatalyst in absolute ethanol. The mixture was hydrogenated at 40 p.s.i.overnight. The reaction mixture was filtered and the filtrate wasconcentrated to dryness. The resulting residue was purified by a silicagel column, eluting with 92/8/0.8 of CH₂ Cl₂ /methanol/ammoniumhydroxide. The product fractions were combined and evaporated todryness. The title compound was obtained as a white solid from ether andwas dried in vacuo, overnight.

m.p.: 99°-158° C.

NMR: Consistent with structure

HPLE: >94% pure

MS: M+H⁺ =557.3 (FAB)

CHN: Calc'd for C₃₀ H₄₄ N₄ O₄ S.0.25 C₄ H₁₀ O. H₂ O; C, 64.11; H, 8.18;N, 9.65. Found: C, 64.12; H, 8.01; N, 9.32.

EXAMPLE 6 ##STR15##

The procedure of Example 2 was carded out using the product of Example 10.33 mmol!, triethylamine 0.88 mmol!, and substituting L-leucine methylester 0.35 mmol! for histidine methyl ester dihydrochloride.Chromatographic elution for column 1 was with 95/5/0.5 of CH₂ Cl₂/methanol/ammonium hydroxide. For column 2, the elution was done with 1%methanol in CH₂ Cl₂. The title compound was obtained as a white solidfrom ether and dried in vacuo, overnight.

106°-128° C.

NMR: Consistent with structure

HPLE: >94% pure

MS: M+H⁺ =542.3 (FAB)

CHN: Calc'd for C₃₀ H₄₃ N₃ O₄ S; C, 66.51; H, 8.00; N, 7.76. Found: C,66.24; H, 8.10; N, 7.49.

EXAMPLE 7 ##STR16##

The procedure of Example 2 was carried out using the product of Example1 0.23 mmol!, triethylamine 0.73 mmol!, and substituting sarcosine ethylester 0.29 mmol! for histidine methyl ester dihydrochloride.Chromatographic elution for column 1 was with 1% ether in CH₂ Cl₂ andthen with 5% methanol in CH₂ Cl₂. For column 2, elution was done with25% ethyl acetate in hexane. The title compound was obtained as a whitesolid from ether and dried in vacuo, overnight.

m.p.: 89°-152° C.

NMR: Consistent with structure

HPLE: >96% pure

MS: M+H⁺ =500 (FAB)

CHN: Calc'd for C₂₇ H₃₇ N₃ O₄ S.0.10 C₄ H₁₀ O.0.40 H₂ O; C, 63.99; H,7.60; N, 8.17. Found: C, 63.95; H, 7.37; N, 7.92.

EXAMPLE 8 ##STR17##

The procedure of Example 2 was carried out using the product of Example1 1.16 mmol!, triethylamine 1.56 mmol!, and substitutingmethyl(2-amino-3-(t-Boc-amino)) propanoate 1.27 mmol! for histidinemethyl ester dihydrochloride. Chromatographic elution for column 1 waswith 5% ether in CH₂ Cl₂ and then with 3% methanol in CH₂ Cl₂. Forcolumn 2, elution was done with 1% methanol in CH₂ Cl₂. The titlecompound was obtained as a white solid from ether and dried in vacuo,overnight.

m.p.: 104°-176° C.

NMR: Consistent with structure

HPLE: >97% pure

MS: M+H⁺ =615 (FAB)

CHN: Calc'd for C₃₂ H₄₆ N₄ O₆ S.0.10 C₄ H₁₀ O.0.45 H₂ O; C, 61.73; H,7.66; N, 8.89. Found: C, 61.68; H, 7.66; N, 8.97.

EXAMPLE 9 ##STR18##

The procedure for Example 2 was carried out using the product of Example1 0.27 mmol!, triethylamine 0.76 mmol!, and substituting glutamicacid-α-methyl ester-α-methyl ester-α-t-butylester 0.308 mmol! forhistidine methyl ester dihydrochloride. Chromatographic elution forcolumn 1 was with 5% ether in CH₂ Cl₂ and then with 5% methanol in CH₂Cl₂. For column 2, elution was done with 4% methanol in CH₂ Cl₂. Thetitle compound was obtained as a white solid from ether and dried invacuo, overnight.

m.p.: 94°-117° C.

NMR: Consistent with structure

HPLE: >93% pure

MS: M+H⁺⁼ 614 (FAB)

CHN: Calc'd for C₃₃ H₄₇ N₃ O₆ S.0.10 C₄ H₁₀ O.0.50 H₂ O; C, 63.65; H,7.84; N, 6.67. Found: C, 63.68; H, 7.64; N, 6.67.

EXAMPLE 10 ##STR19##

The procedure of Example 2 was carried out using the product of Example1 0.22 mmol!, triethylamine 0.60 mmol!, and substituting D-tryptophanmethyl ester 0.24 mmol! for histidine methyl ester dihydrochloride.Chromatographic elution for column 1 was with 1% ether in CH₂ Cl₂ andthen with 5% methanol in CH₂ Cl₂. For column 2, elution was done with 4%methanol in CH₂ Cl₂. The title compound was obtained as a white solidfrom ether and dried in vacuo, overnight.

m.p.: 111°-176° C.

NMR: Consistent with structure

HPLE: >92% pure

MS: M+H⁺ =615.2 (FAB)

CHN: Calc'd for C₃₅ H₄₂ N₄ O₄ S.0.50 C₄ H₁₀ O.0.85 H₂ O; C, 66.62; H,7.29; N, 8.49. Found: C, 66.64; H, 6.93; N, 8.12.

EXAMPLE 11 ##STR20##

The procedure of Example 12 was carried out using the product of Example1 1.38 mmol!, triethylamine 3.40 mmol!, and substituting glycine methylester hydrochloride 1.54 mmol! for histidine methyl esterdihydrochloride. Chromatographic elution for column 1 was with 1% etherin CH₂ Cl₂ and then with 4% methanol in CH₂ Cl₂. For column 2, theelution was done with 99/1/0.1 of CH₂ Cl₂ /methanol/ammonium hydroxide.The title compound was obtained as a white solid from ether and dried invacuo, overnight.

m.p.: 230°-239° C.

NMR: Consistent with structure

HPLE: >92% pure

MS: M+H⁺ =486 (FAB)

CHN: Calc'd for C₂₆ H₃₅ N₃ O₄ S.0.10 C₄ H₁₀ O.0.20 H₂ O; C, 63.84; H,7.39; N, 8.46. Found: C, 63.77; H, 7.39; N, 8.50.

EXAMPLE 12 ##STR21##

Succinic anhydride (12 mg, 0.12 mmols) andendo-(1S)-1'-(((2-amino-7,7-dimethylbicyclo-(2.2.1)-hept-1-yl)methyl)sulfonyl)spiro(1H-indane-1,4'-piperidine)(50 mg, 0.12 mmols) were combined in a mixture of THF (1 mL) andmethylene chloride (1 mL) and stirred at ambient temperature foreighteen hours. The solvents were removed under vacuum and the residuewas treated with trifluoroacetic anhydride (1 mL) and toluene (2 mL),then heated to reflux for 15 minutes while the excess trifluoroaceticanhydride was allowed to boil out. The mixture was then cooled andevaporated to dryness in vacuo. The residue was chromatographed onsilica gel (8" column, 0.5" diam.), eluted with 0.5% (100 mL) followedby 1% (100 mL) methanol in methylene chloride. The product fractionswere combined and evaporated to dryness in vacuo. The residue wasdissolved in ethyl acetate, diluted with hexane, and allowed to standwhereupon the title compound was deposited as a white solid. Thismaterial was filtered and dried in vacuo at 90° for eighteen hours.

m.p.: 228.5°-229.5° C.

¹ H-NMR: Consistent with structure, ca. 0.1 mol of ethyl acetate and ca0.05 mol of hexane observed

TLC: (2% MeOH in CH₂ Cl₂) single component, R_(f) =0.66

MS: M+H⁺ =485 (FAB)

CHN: Calc'd for C₂₇ H₃₆ N₂ O₄ S.0.10 C₄ H₈ O₂.0.05 C₆ H₁₄ ; C, 66.83; H,7.59; N, 5.63. Found: C, 66.62; H, 7.61; N, 5.51.

EXAMPLE 13 ##STR22##

To a 0° C. solution ofendo-(1S)-1'(((2-amino-7,7-dimethylbicyclo(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1,4'-piperidine)(0.90 g; 2.2 mmol) and diisopropylethylamine (DIEA) (0.47 mL; 2.7 mmol)in CHCl₃ (50 mL) was added iodoacetonitrile (0.38 grams; 2.3 mmol). Thesolution was stirred for 1 h at 0° C. and then for 18 h at ambienttemperature. The mixture was extracted with aqueous NaHCO₃ (2×25 mL),dried (MgSO₄), filtered, and the solvent was removed under reducedpressure. The residue was purified by pressurized silica gel columnchromatography using 1:3 ethyl acetate-hexanes as eluant (TLC Rf=0.30 in1:3 ethyl acetate-hexanes; HPLC retention time=9.30 min). The purifiedcyanomethylated amine (0.80 g; 1.8 mmol) was dissolved in2-methoxyethanol (15 mL) and to the stirred solution was added Raneynickel alloy (2.5 grams) followed by 6N NaOH solution (2.0 mL, 12 mmol).The mixture was heated to 8020 C. on a steam bath and then stirred atambient temperature for 14 h. The catalyst was removed by filtrationthrough Celite and washed with EtOAc. The filtrate solvents were removedunder reduced pressure and the residue was taken up in CHCl₃ (50 mL) andwashed with water (2×25 mL). The organic phase was dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified by pressurized silica gel column chromatography using 92:8:0.8CHCl₃ :MeOH:NH₄ : OH as eluant (TLC Rf=0.25 in 92:8:0.8 : CHCl₃:MeOH:NH₄ OH; HPLC retention time=7.20 min; FAB mass spectrum m/z=446).The purified diamine (0.51 g; 1.1 mmol) was dissolved in CHCl₃ and tothe solution was added 1,1'-carbonyldiimidazole (0.19 g; 1.2 mmol).After the solution had been stirred for 1 h at ambient temperature,acetic acid (0.63 mL; 11 mmol) was added and the solution was refluxedfor 6 h. The reaction was cooled and the solvent was removed underreduced pressure. The residue was dissolved in EtOAc (50 mL) and thesolution was washed with 10% aqueous citric acid (25 mL), water (25 mL),and aqueous NaHCO₃ (25 mL). The organic phase was dried (MgSO₄),filtered, and the solvent was removed under reduced pressure. Theresidue was purified by pressurized silica gel column chromatographyusing 1:3 EtOAc:CHCl₃ as eluant. The title compound was obtained as awhite foam from

CHCl₃ (TLC R_(f) =0.27 in 1:4 EtOAc:CHCl₃ ;

HPLC retention time=10.67 min;

FAB mass spectrum m/z=472; calc for C₂₆ H₃₇ N₃ O₃ S-0.70 CHCl₃ : C,57.76; H, 6.84; N, 7.75. Found: C, 57.84; H, 6.82; N, 7.42;

¹ H NMR (CDCl₃, 300 MHz) δ7.15-7.25 (m, 4H), 4.39 (ddd, J=2.3, 5.3, 12.0Hz, 1H) 1.05 (s, 3H), 1.00 (s, 3H)).

HPLC conditions: 12 cm C₁₈ reverse phase Vydac column; 15 min gradient95:5 to 0:100 A:B (A=H₂ O containing 0.1% TFA, B=CH₃ CN containing 0.1%TFA), flow rate=2.0 mL/min, detection at 215 nm.

EXAMPLE 14 ##STR23##

2-Amino- 1- (2,3 -dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!methyl!-7,7-dimethylbicyclo2.2.1!hept-2-yl!-4-(methyl-sulfonyl)-but-1-ylamine (250 mg, 0.425 mmole)and thiocarbonyldiimidazole (76 mg, 0.425 mmole) were combined with 500mg of anhydrous cesium carbonate in 12 ml of dry N,N'-dimethylformamideat room temperature. The orange suspension was stirred for 2 hours,filtered, and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate (100 ml) and sodium bicarbonatesolution. The phases were separated and the organic phase was washedwith saturated sodium bicarbonate solution (3×40 ml) and brine, thendried (sodium sulfate) and concentrated. The crude product was (250 mg)was obtained as an oil which crystallized on standing in methanol

NMR: Consistent with structure and verifies presence of solvent;

HPLC: >97% pure at 214 nm;

FAB MS: 594 (M++H);

Elem. Anal. calc'd for C₂₉ H₄₃ N₃ O₄ S₃.1.05 CH₃ OH.0.25H₂ O: Calc'd: C,57.10; H, 7.61; N, 6.65. Found: C, 57.11; H, 7.21; N, 6.28.

EXAMPLE 15

1- 1- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!-7,7-dimethylbicyclo2.2.1!hept-2-yl!-2,5-dioxo-3-pyrrolidineacetic acid ##STR24##

2-Carboxymethylsuccinic anhydride(3-carboxymethyl-tetrahydrofuran-2,5-dione) was prepared fromtricarballylic acid as described in J. Org. Chem. 46 2866 (1981).2-Carboxymethylsuccinic anhydride (0.93 g, 5.88 mmols) andendo-(1S)-1'-(((2-amino-7,7-dimethylbicyclo-(2.2.1)-hept-1-yl)methyl)sulfonyl)-spiro(1H-indene-1,4'-piperidine)(2.4 g, 5.97 mmols) were combined in DMF (20 mL) and stirred at ambienttemperature for eighteen hours. The DMF was removed under vacuum and theresidue was treated with 1N HCl and extracted with methylene chloride.The methylene chloride layers were combined, dried over sodium sulfate,filtered, and evaporated to dryness in vacuo. The residue was treatedwith toluene (100 mL) and trifluoroacetic anhydride (5mL), and theresulting mixture was heated to reflux for 2-4 min while the excesstrifluoroacetic anhydride was allowed to boil out. Reflux was continuedfor 10 min, and the mixture was then cooled and evaporated to dryness invacuo. The residue was chromatographed on silica gel (10" column, 2"diam.), eluted with 200:10:1:1 CH₂ Cl₂ :MeOH:HoAc:H₂ O. The productobtained by evaporation of the eluate was rechromatographed on silicagel twice, once eluted with 1L each of 1000:10:1:1, 500:10:1:1, and330:10:1:1 CH₂ Cl₂ :MeOH:HoAc:H₂ O, and the second time with 600:10:1:1of the same solvents. The combined product fractions were evaporated todryness in vacuo, treated with ether and re-evaporated 3 times, thentreated with hexane and evaporated to obtain the title compound as asolid which was dried in vacuo at 400° C. for eighteen hours.

M.P.: 80°-100° C. (foam;indistinct)

HPLC: 100%

¹ H-NMR: Consistent with structure, ca. 0.05 mol of DMF and ca. 0.18 molof hexane observed.

TLC: (490:10:1:1 CH₂ Cl₂ :MeOH:HoAc:H₂ O) single component, R_(f) =0.25.

M.S.: (FAB) M+H @543

Analysis for C₂₉ H₃₈ N₂ O.0.05 C₃ H₇ NO.0.18 C₆ H₁₄.0.3 H₂ O: Calc'd: C,64.00; H, 7.37; N, 5.0 Found: C, 64.01; H, 7.30; N, 5.12.

EXAMPLE 16 ##STR25##

To a 0° C. stirred solution of p-nitrophenyl chloroformate (1.37 g; 6.8mmol) in CHCl₃ (100 mL) was added DIEA (1.18 ml; 12.4 mmol) and theproduct of Example A (2.5 g; 6.2 mmol). The solution was stirred at 0°C. for 1 h and then at ambient temperature for 14 h. The reactionmixture was concentrated under reduced pressure, the residue wasdissolved in CHCl₃ (100 mL) and washed with 5% aqueous HCl (2×50 mL) andaqueous NaHCO₃ (100 mL). The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The urethane wasobtained as a white foam.

TLC: R_(f) 0.35 (1:3 EtOAc:hexanes)

HPLC (method A): retention time 12.3 min

To a 0° C. stirred solution of the p-nitrophenyl urethane (2.8 g; 5.0mmol) in DMF (20 mL) was added methyl 1-methyl-4-amino-4-piperidinecarboxylate hydrochloride (1.04 gm, 5 mmol) and DIEA (0.87 ml, 5 mmol).The solution was stirred for 2 hours at ambient temperature. Thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in CHCl₃ (100 mL) and washed with 5% aqueous HCl (2×50 mL)and 10 % aqueous Na₂ CO₃ (5×100 mL). The organic phase was dried(MgSO₄), filtered, and the solvent was removed under reduced pressure.The urea was obtained as a foam which was crystallized from EtOAc (1.14gm, 2 mmol).

Analysis calculated for (C₃₁ H₄₄ N₄ O₄ S).1.85 H₂ O C 60.61 H 8.22 N8.84 Found: C 60.58 H 8.02 N 8.80

TLC: R_(f) 0.2 (95:5:0.5 CHCl₃ :MeOH:NH₃ OH)

HPLC (method A): retention time 9.17 min

FAB MS: m/z 601 (M⁺ +H)

To a 0° C. stirred solution of the urea (1.0 gm, 1.67 mmol) in MeOH (50mL) was added in small portions NaH (dry powder) (0.125 gm, 5 mmol). Thesolution was stirred for 2 hours. The reaction mixture was neutralizedwith acetic acid and evaporated under reduced pressure. The residue wasdissolved in CHCl₃ (100 mL) and washed with 5% aqueous HCl (2×50 mL) andaqueous NaHCO₃ (100 mL). The organic phase was dried (MgSO₄), filtered,and the solvent was removed under reduced pressure. The title compoundwas obtained as a foam which was precipitated from EtOAc/hexanes (0.260gm, 0.5 mmol).

Analysis calculated for (C₃₁ H₄₄ N₄ O₄ S).0.3 EtOAc C 64.98 H 7.86 N9.41 Found: C 64.65 H 7.76 N 9.46

TLC: R_(f) 0.35 (95:5:0.5 CHCl₃ MeOH:NH₄ OH)

HPLC (method A): retention time 10.17 min

FAB MS: m/z 569 (M⁺ +H)

¹ H NMR (300 MHz, CDCl₃): d 7.15-7.25 (m, 4H), 5.8 (s, 1H), 4.49 (m,1H), 2.3 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H)

EXAMPLE 17 ##STR26##

To a 0° C. solution of the unsubstituted hydantoin product of Example 11(1.50 g; 3.09 mmol) and 4-chloromethyl-1-(triphenyl)methylimidazole(1.39 g; 3.87 mmol) in dry THF (60 mL) under an atmosphere of argon wasadded NaH (154 mg of a 60% suspension in mineral oil; 3.86 mmol). Themixture was stirred at 0° C. for 1 h, and then at ambient temperaturefor 24 h. Several drops of acetic acid were added and the mixture wasconcentrated under reduced pressure. The residue was dissolved in EtOAc(100 mL) and washed with aqueous NaHCO₃ (2×50 mL). The organic phase wasdried (MgSO₄), filtered and concentrated under reduced pressure. Theresidue was purified by pressurized silica gel column chromatographyusing 1:1 EtOAc:CHCl₃ as eluant. The product (1.40 g; 1.73 mmol) washeated in 10 mL of MeOH containing 10 mL of 6N HCl at 60° C. for 6 h.The solvents were removed under reduced pressure and the residue wasdissolved in CHCl₃ (100 mL) and washed with aqueous NaHCO₃ (2×50 mL).The organic phase was dried (MgSO₄), filtered, and concentrated underreduced pressure. The residue was purified by pressurized silica gelcolumn chromatography using 95:5:0.5 CHCl₃ :MeOH:NH₄ OH as eluant. Thepurified product was dissolved in MeOH containing 3 equivalents of 6NHCl and the solvent was removed under reduced pressure. The residue wastaken up in water-dioxane and lyophilized to give the HCl salt of titlecompound as a white powder.

Analysis calculated for (C₃₀ H₃₉ N₅ O₄ S).2.05 HCl.0.55 H₂ O C, 57.40;H, 6.53; N, 10.77 Found: C, 57.44; H, 6.53; N, 10.41

TLC: R_(f) 0.29 (95:5:0.5 CHCl₃ :MeOH:NH₄ OH)

HPLC (method A): retention time 9.43 min

FAB MS: m/z 566 (M⁺ +H)

¹ H NMR (300 MHz, CDCl₃): δ8.95 (s, 1H), 7.40 (s, 1H), 7.15-7.25 (m,4H), 4.75 (m, 2H), 4.55 (m, 1H), 1.03 (s, 3H), 0.97 (s, 3H)

EXAMPLE 18 ##STR27##

To a stirred solution of the hydantoin (150 mg; 0.309 mmol) in a mixtureof 2:1 allyl bromide:tetrahydrofuran (30 mL) was added sodium hydride(12 mg; 60% dispersion in oil). The temperature was then increased toreflux. After 1 hr the solution was cooled, then concentrated.Purification by flash chromatography (5% methanol in methylene chloride)provided the intermediate allyl derivative (158 mg).

The allyl hydantoin described above (105 mg; 0.20 mmol) was dissolved ina solution of 1:1 pyridine:toluene (12 mL). While stirring at roomtemperature, osmium tetraoxide (51 mg; 0.20 mmol) was added. After 8 hr10 mL of a saturated aqueous solution of sodium bisulfite was added. Thesolution was allowed to stir for 1 hr, then diluted with ethyl acetate(50 mL). The ethyl acetate was separated, dried over sodium sulfate,then concentrated. Purification of the residue by flash chromatography(10% methanol in methylene chloride) afforded the title compound (39 mg;35%).

Analysis calculated for (C₂₉ H₄₁ N₃ O₆ S).0.56 H₂) C, 61.13; H, 7.45; N,7.37 Found: C, 61.15; H, 7.55; N, 7.15

HPLC (Vydac C18 Column; gradient from 95/5 to 0/100 H₂ O/CH₃ CN with0.1% TFA. 15 min. gradient, flow rate=1.5 ml/min.) R_(t) =12.12 min.Purity=96%

¹ HNMR: Consistent with structure

FABMS: m/z=560 (M⁺ +H)

EXAMPLE 19 ##STR28##

To a stirred solution of N-methyliminodiacetic acid (220 mg; 1.50 mmol)in DMF (10 mL) was added DIEA (0.575 mL; 3.30 mmol) and BOP (665 mg;1.50 mmol). The mixture was stirred at ambient temperature for 24 h, andthen the product of Example A (500 mg; 1.24 mmol) was added. The mixturewas strirred at ambient temperature for 24 h and then the solvent wasremoved under reduced pressure. The residue was dissolved in EtOAc (50mL) and washed with 10% aqueous citric acid (20 mL) and water (10 mL).The organic phase was dried (MgSO₄), filtered, and the solvent wasremoved under reduced pressure. The residue was purified by pressurizedsilica gel column chromatography using a gradient elution of 5-10%MeOH--CHCl₃. The purified monoacid, monoamide was obtained as a whitefoam.

TLC: R_(f) 0.40 (90:10 CHCl₃ :MeOH)

HPLC (method A): retention time 9.03 min

FAB MS: m/z 532 (M⁺ +H)

The purified monoacid, monoamide (150 mg; 0.282 mmol) was heated toreflux in a solution of THF (5 mL) and acetic anhydride (1mL) for 14 h.The solvents were removed under reduced pressure and the residue waspurified by pressurized silica gel column chromatography using 1:4EtOAc-hexanes as eluant. The title compound was obtained as a white foamfrom ether.

Analysis calculated for (C₂₈ H₃₉ N₃ O₄ S).0.2 ether.0.1 H₂ O C, 65.23;H, 7.83; N, 7.92; Found: C, 65.10; H, 7.99; N, 7.95;

TLC: R_(f) 0.29 (1:2 EtOAc:hexanes)

HPLC (method A): retention time 10.57 min

FAB MS: m/z 514 (M⁺ +H)

¹ H NMR (300 MHz, CDCl₃): δ7.10-7.25 (m, 4H), 5.20 (ddd, J=2.2, 5.9,12.1 Hz, 1H), 3.40 (s, 3H), 2.37 (s, 3H), 1.06 (s, 3H), 0.95 (s, 3H)

EXAMPLE 20 ##STR29##(1S)-1'-(((2-endo-Amino-7,7-dimethylbicyclo-(2.2.1)hept-1-yl)methyl)sulfonyl)spiro(1H-indane-1,4'-piperidine)(1.5 g, 3.7 mmole), tert-butylbromo acetate (0.8 g, 4.1 mmole), andcrushed potassium carbonate (0.57 g, 4.1 mmole) were combined in 80 mlof absolute ethanol and heated at reflux for 12 hours. The reactionmixture was cooled, filtered, and rotoevaporated under reduced pressure.The residual material was partitioned between ethyl acetate and water.The phases were separated and the organic layer was washed in successionwith saturated sodium bicarbonate solution and brine, then dried (sodiumsulfate), and concentrated to give a semi-solid. The crude product wascrystallized from ethyl acetate to give 0.85 g of(1S)-1'-(((2-endo-tert-butyloxycarbonylmethylamino-7,7-dimethylbicyclo-(2.2.1)hept-1-yl)methyl)sulfonyl)spiro(1H-indane-1,4'-piperidine).Concentration of the mother liquors afforded an additional 0.99 g ofmaterial.

A solution of 40 ml of methylene chloride containing 0.41 ml oftriethylamine and 0.97 g of(1S)-1'-(((2-endo-tert-butyloxycarbonylmethylamino-7,7-dimethylbicyclo(2.2.1)hept-1-yl)methyl)sulfonyl)spiro(1H-indane-1,4'-piperidine)was stirred magnetically in an ice bath and treated in one portion with0.24 ml of bromoacetylbromide. After 1 hour, an additional equivalenteach of bromoacetylbromide and triethylamine were added and the reactionmixture was stirred at ambient temperature overnight. The reactionmixture was diluted with methylene chloride and washed in successionwith sodium bicarbonate solution, 10% citric acid solution, and brine.The dried extracts were concentrated and the residual material was flashchromatographed on silica gel (15% ethyl acetate-hexane) to give 0.74 gof 2-tert-butyloxycarbonylmethylamino-N- 1- (2,3-dihydro-spiro1H-indane-1,4'-piperidin!-1'-yl)sulfonyl!methyl!-7,7-dimethyl-bicyclo2.2.1!hept-2-yl!-bromoacetamide.

A continuous stream of ammonia gas was passed for 10 minutes into an icecold solution of methanol (32 ml) containing 0.64 g (1.0 mmole) of2-tert-butyloxycarbonylmethylamino-N- 1- (2,3-dihydrospiro1H-indane-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!-7,7-dimethylbicyclo2.2.1!hept-2-yl!-bromoacetamide. The reaction mixture was warmed to roomtemperature and stirred for 1 hour. All volatile components were removedunder reduced pressure to give a semi-solid which was partitionedbetween ethyl acetate and water. The organic phase was washed with water(3×) and brine, then dried (sodium sulfate) and concentrated. Triturateof the residual material with ether gave 0.32 g of the title compound asan off-white solid m.p. >220° C.;

NMR: Consistent with structure:

HPLC: >99% pure at 214 nm;

FAB MS: 500 (M⁺ +H);

Elem. Analysis calculated for C₂₇ H₃₇ N₃ O₄ S.0.25 H₂ O: C, 64.31; H,7.51; N, 8.34. Found: C, 64.32; H, 7.34; N, 8.14.

EXAMPLE 21 ##STR30##

To an ice cold suspension of trimethylsulfoxonium iodide (610 mg, 2.77mmole) in 10 ml of dry tetrahydrofuran was added 1.8 ml of 1.6Mn-butyllithium under nitrogen. After addition was complete the resultingreaction mixture was stirred at ambient temperature for 2 hours,re-cooled to 0° C., and treated with a tetrahydrofuran solution (6 ml)containing 620 mg (1.55 mmole) of (1S)-1'-(((7,7-dimethyl-2-oxobicyclo2.2.1!hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine). Thereaction mixture was then stirred at ambient temperature overnight. Thereaction mixture was concentrated under reduced pressure to a volume of6 ml and chromatographed on silica gel (hexane-ethyl acetate, 4:1)separating unreacted starting material and affording 390 mg of(1S)-1'-(((7,7-dimethyl-2-oximinobicyclo-2.2.1!hept-1-yl)methyl)sulfonyl)spiro-(1H-indene-1,4'-piperidine).

To a suspension of 1.7 mmole of sodium hydride in 1.7 ml of dryN,N'-dimethylformamide was added 0.18 mmole of succinimide. Afterstirring for 15 minutes the reaction mixture became homogeneous and 70mg (0.17 mmole) of (1S)-1'-(((7,7-dimethyl-2-oximinobicyclo-2.2.1!hept-1-yl)methyl)sulfonyl)spiro-(1H-indene-1,4'-piperidine) wasadded. The reaction mixture was heated at 150° C. for 4 hours, thencooled to room temperature, and diluted with ethyl acetate. The organicphase was washed with water and brine, then dried, and concentrated togive 92 mg of crude product. Flash column chromatography on silica gel(30% ethyl acetate-hexane elution) of the crude reaction productafforded the title compound in analytically pure form as a white solidm.p. 111°-115° C.;

NMR: Consistent with structure:

HPLC: >99% pure at 214 nm;

FAB MS: 513 (M⁺ +H), 621 (M⁺ +thioglycerol);

Elem. Analysis calculated for C₂₈ H₃₆ N₂ O₅ S.0.75 H₂ O C, 63.90; H,7.20; N, 5.32. Found: C, 63.86; H, 7.14; N, 5.10.

EXAMPLE 22 ##STR31##

To a 0° C. solution of the unsubstituted hydantoin product of Example 11(1.50 g; 3.09 mmol) and iodoacetonitrile (1.03 g; 6.18 mmol) in dry THF(30 mL) under an atmosphere of argon was added NaH (185 mg of a 60%suspension in mineral oil; 4.64 mmol). The mixture was stirred at 0° C.for 1 h, and then at ambient temperature for 6 h. The reaction wascooled to 0° C. and more iodoacetonitrile (0.52 g; 3.1 mmol) and NaH(124 mg of a 60% suspension in mineral oil; 3.1 mmol) were added. Themixture was stirred at 0° C. for 1 h, and then at ambient temperaturefor 14 h. Several drops of acetic acid were added and the dark brownmixture was concentrated under reduced pressure. The residue wasdissolved in EtOAc (100 mL) and washed with aqueous NaHCO₃ (2×50 mL).The organic phase was dried (MgSO₄), filtered and concentrated underreduced pressure. The residue was purified by pressurized silica gelcolumn chromatography using 7:3 hexane:EtOAc as eluant, and then bypreparative reverse phase HPLC using a water-acetonitrile gradientcontaining 0.1% TFA. The title compound was obtained as a lyophilizedpowder.

Analysis calculated for (C₂₈ H₃₆ N₄ O₄ S).0.35 TFA.0.25 H₂ O C, 60.51;H, 6.44; N, 10.22 Found: C, 60.57; H, 6.53; N, 9.85.

TLC: R_(f) 0.43 (3:2 hexane:EtOAc)

HPLC (method A): retention time 11.39 min

FAB MS: m/z 525 (M⁺ +H)

¹ H NMR (300 MHz, CDCl₃): δ7.1-7.3 (m, 4H), 4.56 (m, 1H), 4.35 (ABquartet, J=18 Hz, 2H), 3.95 (AB quartet, J=16 Hz, 2H), 1.06 (s, 3H),0.97 (s, 3H)

EXAMPLE 23 ##STR32##

To a stirred solution ofendo-(1S)-1'(((2-amino-7,7-dimethylbicyclo(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1,4'-piperidine(526 mg; 1.31 mmol) in methylene chloride (20 mL) was addeddiacetyl-L-tartaric anhydride (312 mg; 1.44 mmol), followed bydiisopropylethyl amine (0.251 mL; 1.44 mmol). After 18 hr the solutionwas concentrated, then partitioned between ethyl acetate (200 mL) and 1MHCl (200 mL). The ethyl acetate layer was washed with additional water(2×200 mL), then dried over sodium sulfate and concentrated. Partialpurification by flash chromatography (10% methanol in methylenechloride) afforded material that was dissolved in methylene chloride (20mL) and treated with thionyl chloride (0.096 mL; 1.31 mmol). Afterstirring at room temperature for 18 hr, the solution was concentrated.The intermediate diacetate was obtained by purification of the residueby flash chromatography (10% methanol in methylene chloride).

The diacetate described above (1 g; 1.66 mmol) was dissolved in asolution of 3:1 tetrahydrofuran:water (40 mL) then cooled to 0° C. Asolution of 30% hydrogen peroxide (0.832 mL; 6.64 mmol) was addedfollowed by lithium hydroxide (80 mg; 3.32 mmol). After stirring at 0°C. for 30 min the solution was concentrated. The title compound (492 mg;73%) was obtained through purification of the residue by flashchromatography (10% methanol in methylene chloride).

Analysis calculated for (C₂₇ H₃₆ N₂ O₆ S).0.35 H₂ O C, 62.01; H, 7.07;N, 5.36 Found: C, 62.00; H, 6.86; N, 5.47

HPLC: (Vydac C18 Column; gradient from 95/5 to 0/100

H₂ O/CH₃ CN with 0.1% TFA. 15 min. gradient, flow rate=1.5 ml/min.)R_(t) =12.5 min. Purity=100%

¹ HNMR: Consistent with structure

FABMS: m/z=517 (M⁺ +H)

EXAMPLE 24

1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2-propen-1-yl!-2,5-dioxo-1-imidazolidine##STR33##

To a stirred solution of 1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-2,5-dioxo-1-imidazolidine (150 mg; 0.309 mmol) intetrahydrofuran (20 mL) was added allyl bromide (27 μL; 0.309 mmol),followed by sodium hydride (12 mg; 60% dispersion in oil). Thetemperature was increased to reflux. After 4 h the solution was cooledthen concentrated. Purification by flash chromatography (5% methanol inmethylene chloride) provided the title compound as a white solid (81mg).

1HNMR: consistent with structure.

M.P.: 101°-104° C.

HPLC: Rt=14.7 min; 95%

FABMS: M+1 at 526

Analysis calculated for C₂₉ H₃₉ N₃ O₄ S+0.05 CH₂ Cl₂ +0.40 H₂ O C,64.95; H, 7.49; N, 7.82 Found: C, 64.93; H, 7.48; N, 7.43

EXAMPLE 25

1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2-hydroxy-3-1,1-dimethylamino!-propan-1-yl!-2,5-dioxo-1-imidazolidine ##STR34##

To a stirred solution of 1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-2,5-dioxo-1-imidazolidine (164 mg; 0.338 mmol) intetrahydrofuran (2 mL) was added bromoepihydrin (1 mL), followed bysodium hydride (12 mg; 60% dispersion in oil). The mixture was thenheated to reflux. After 6 hours, the mixture was cooled andconcentrated. Purification by flash chromatography (30% ethyl acetate inpetroleum ether as eluent) afforded 1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2,3oxirane-1-propenyl!-2,5-dioxo-1-imidazolidine as a white foam (141 mg).

To a solution of 1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2,3oxirane-1-propenyl!-2,5-dioxo-1-imidazolidine (73 mg; 0.135 mmol) inabsolute ethanol (2 mL) was added dimethylamine hydrochloride (55 mg;0.68 mmol) and diisopropylethylamine ((47 μL). After 6 hours at reflux,the solution was cooled and concentrated. Purification by preparativeHPLC afforded the title compound (41 mg).

¹ HNMR: consistent with structure.

M.P.: 93°-97° C.

HPLC: Rt=11.63 min; 99%

FABMS: M+1 at 587

Analysis calculated for C₃₁ H₄₆ N₄ O₅ S+0.65 CH₂ Cl₂ +0.20 H₂ O C,58.88; H, 7.45; N, 8.08 Found: C, 58.90; H, 7.46; N, 8.53

EXAMPLE 26

1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2,5-dioxo-3S-4-aminopropylamido!!-1-succinimide ##STR35##

To a solution of endo- 1S!-1' 2-amino-7,7-dimethylbicyclo2.2.1!-hept-1yl!-methyl!-sulfonyl!spiro 1H-indan-1-4'-piperidine!(1 g,2.48 mmol) in methylene chloride (75 mL) was added Boc-(L)-Aspartic acidβ-methyl ester (675 mg, 2.72 mmol), hydroxybenzotriazole (436 mg, 3.22mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(618 mg, 3.22 mmol). After 4 hours the solution was concentrated, thenpartitioned between ethyl acetate and 1M NaOH (75 mL each). The organiclayer was washed with 1M HCl, and brine (75 mL each) then dried over Na₂SO₄. The solution was filtered and concentrated. Purification by flashchromatography (40% ethyl acetate in petroleum ether as eluent) gave anamide ester intermediate as white foam (1.15 g).

The foam was dissolved in dry tetrahydrofuran (100 mL) under nitrogenatmosphere, then cooled to -78° C. Lithium hexamethyldisilylazide (3.64mL, 1M solution in tetrahydrofuran) was added dropwise. After 4 hours, asaturated solution of ammonium chloride was added, and the reactionmixture was allowed to warm to room temperature. The mixture waspartitioned between ethyl acetate and water (75 mL each). The ethylacetate layer was dried over sodium sulfate, then concentrated.Purification by flash chromatography (gradient from 15% to 20% ethylacetate in petroleum ether as eluent) afforded a protectedaminosuccinimide intermediate as a white foam (1.1 g).

To a solution of the aminosuccinimide (1.46 g, 2.43 mmol) in ethylacetate (50 mL) was introduced a stream of HCl gas. After 15 min. theHCl was removed and the solution was washed with 1M sodium carbonate.The ethyl acetate layer was dried over sodium sulfate, filtered, andconcentrated. Purification by flash chromatography (a gradient from 2%to 10% methanol in methylene chloride as eluent) afforded anintermediate unprotected aminosuccinimide as a white foam (1.12 g).

To a solution of the unprotected aminosuccinimide (90 mg, 0.18 mmol) inmethylene chloride (15 mL) was added Boc-b-alanine (51 mg, 0.27 mmol),hydroxybenzotriazole (37 mg, 0.27 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27mmol), and diisopropylethylamine (47 μL, 0.27 mmol). After stirring atroom temperature for 6 hours the mixture was concentrated, thenpartitioned between ethyl acetate and 1M HCl (200 mL each). The ethylacetate layer was dried over sodium sulfate, then filtered andconcentrated. Purification by preparative HPLC afforded an adduct whichwas dissolved in methylene chloride (20 mL) and treated withtrifluoroacetic acid (8 mL). After 1 hour, the solution wasconcentrated, then the product was purified by preparative HPLC to givethe title compound (71 mg).

¹ HNMR: consistent with structure.

HPLC: R_(t) =12.2 min; 97%

FABMS: M+1 at 571

Analysis calculated for C₃₀ H₄₂ N₄ O₅ S+2.5 trifluoroacetic acid C,46.89; H, 5.47; N, 6.83 Found: C, 46.91; H, 5.30; N, 6.77

EXAMPLE 27

1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3 endo- 2,5-dioxo-3S-amino-4-piperidinyl!!-1-succinimide ##STR36##

To a solution of 1R- (2,3-Dihydrospiro1H-indene-1,4'-piperidin!-1'-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3 endo- 2,5-dioxo- 3S-amino!!-1-succinimide (161mg, 0.32 mmol) in methanol (15 mL) was added Boc-4-piperidinone (77 mg,0.39 mmol), and sodium cyanoborohydride (61 mg, 0.96 mmol). Afterstirring at room temperature for 4 hours, the mixture was concentratedand purified by flash chromatography (5% methanol in methylene chlorideas eluent).

The residue was redissolved in methylene chloride (10 mL), then treatedwith trifluoroacetic acid (5 mL). After 2 hours the solution wasconcentrated. Purification by flash chromatography (10% methanol inmethylene chloride as eluent) afforded the title compound (91 mg).

¹ HNMR: consistent with structure.

HPLC: R_(t) =13.2 min; 98%

FABMS: M+1 at 583

Analysis calculated for C₃₂ H₄₆ N₄ O₄ S+1.5 trifluoroacetic acid+1.5 H₂O C, 53.84; H, 6.52; N, 7.18 Found: C, 53.85; H, 6.69; N, 6.79

EXAMPLE 28

1R-4-(2-methylphenyl)piperazin-1-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2R-hydroxy-3-piperazin-1-yl!-propan-1-yl!-2,5-dioxo-1-imidazolidine ##STR37##

To a stirred solution of 1R-4-(2-methylphenyl)piperazin-1-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-2,5-dioxo-1-imidazolidine (120 mg, 0.253 mmol) indry tetrahydrofuran (15 mL) was added 2R-(-)-glycidyl tosylate (288 mg,1.26 mmol), followed by sodium hydride (60% dispersion in oil). Thetemperature was increased to reflux. After 2 hours the mixture wascooled then concentrated. Purification by preparative TLC (40% ethylacetate in petroleum ether as eluent) afforded 1R-4-(2-methylphenyl)piperazin-1-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2S,3oxirane-1-propenyl!-2,5-dioxo-1-imidazolidine as a white foam (112 mg).

To a solution of 1R-4-(2-methylphenyl)piperazin-1-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2S,3oxirane-1-propenyl!-2,5-dioxo-1-imidazolidine (66 mg, 0.12 mmol) inabsolute ethanol (20 mL) was added piperazine (50 mg, 0.58 mmol).

The temperature was increased to reflux. After 2 hours the solution wascooled and concentrated. Purification by flash chromatography (85:15:1methylene chloride:methanol:ammonium hydroxide as eluent) afforded thetitle compound (19 mg).

¹ HNMR: consistent with structure.

HPLC: Rt=10.4 min; 95%

FABMS: M+1 at 517

Analysis calculated for C₃₁ H₄₈ N₆ O₅ S+0.15 hexanes+1.2 H₂ O C, 58.82;H, 8.12; N, 12.90 Found: C, 58.84; H, 7.76; N, 12.54

EXAMPLE 29 ##STR38##

To a solution ofendo-(1S)-1'(((2-amino-7,7-dimethyl-bicyclo(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1,4'-piperidine)(3 g, 7.45 mmol) in methylene chloride (150 mL) was added maleicanhydride (876 mg, 8.94 mmol). After stirring for 2 h at roomtemperature, the mixture was concentrated, then redissolved in aceticanhydride (100 mL). Sodium acetate was added (611 mg, 7.45 mmol), thenthe temperature was increased to reflux. After 48 h, the mixture wascooled to room temperature, then concentrated. Flash chromatographyusing 50% ethyl acetate in petroleum ether afforded 1.5 g of the titlecompound as a white foam.

¹ HNMR: consistent with structure.

HPLC: method A, R_(t) =14.86 min; 96%

FABMS: M+1 at 483

Analysis calculated for C₂₇ H₃₄ N₂ O₄ S+0.35 dioxane C, 66.43; H, 7.22;N, 5.46 Found: C, 66.45; H, 7.25; N, 5.23

EXAMPLE 30 ##STR39##

To a solution of the product of Example 29 (84 mg, 0.17 mmol) in 1:1methylene chloride:diethyl ether (15 mL) was added chloroximidoacetate(32 mg, 0.21 mmol), followed by diisopropylethylamine (37 uL). Themixture was allowed to stir at room temperature for 4 h at which timeadditional chloroximidoacetate was added (32 mg). After 18 h, themixture was concentrated and the residue was applied to preparative TLCplates. Two products were obtained as white solids, in 40% overallyield.

¹ HNMR: consistent with structure.

HPLC: method A, R_(t) =14.73 min; 100%

FABMS: M+1 at 598

Analysis calculated for C₃₁ H₃₉ N₃ O₇ S+0.55 chloroform C, 57.21; H,5.87; N, 6.34 Found: C, 57.18; H, 5.88; N, 6.41

¹ HNMR: consistent with structure.

HPLC: method A, R_(t) =14.99 min; 100%

FABMS: M+1 at 598

Analysis calculated for C₃₁ H₃₉ N₃ O₇ S+0.20 chloroform C, 60.29; H,6.36; N, 6.76 Found: C, 60.27; H, 6.29; N, 6.72

EXAMPLE 31 ##STR40##

To a solution of the product of example 29 (109 mg, 0.23 mmol) inacetonitrile (10 mL) was added silver iodide (57 mg, 0.46 mmol),followed by a solution ofN-benzyl-N-(trimethylsilylmethyl)aminoacetonitrile (111 uL, 0.46 mmol)in acetonitrile (10 mL). After stirring at room temperature in the darkfor 18 h, the mixture was filtered, then concentrated. The titlecompound was obtained in 60% yield by preparative TLC using 25% ethylacetate in petroleum ether as eluent.

¹ HNMR: consistent with structure.

HPLC: method A, Rt=12.21 min; 97%

TLC: R_(f) =0.2 (20% ethyl acetate in petroleum ether)

Analysis calculated for C₃₆ H₄₅ N₃ O₄ S+0.45 water C, 69.30; H, 7.42; N,6.73 Found: C, 69.34; H, 7.39; N, 7.02

EXAMPLE 32 ##STR41##

To a solution of the product of Example 31 (50 mg, 0.081 mmol) inethanol (15 mL) was added palladium black (5 mg), followed by aceticacid (1 drop). After stirring at room temperature under an atmosphere ofhydrogen for 18 h, the mixture was filtered then concentrated. The titlecompound was obtained by preparative HPLC (20 mg).

¹ HNMR: consistent with structure.

HPLC: method A, R_(t) =11.97 min; 97%

TLC: R_(f) =0.5 (10% methanol in methylene chloride)

Analysis calculated for C₂₉ H₃₉ N₃ O₄ S+1.25 trifluoroacetic acid+0.60toluene. C, 59.26; H, 6.28; N, 5.81 Found: C, 59.27; H, 6.26; N, 5.86

EXAMPLE 33 ##STR42##

To a solution of the product of Example 29 (660 mg, 1.37 mmol) in 11tetrahydrofuran:diethyl ether (200 mL) was added an ethereal solution ofdiazomethane (approximately 5 eq.). After stirring at room temperaturefor 1 h, acetic acid (2 drops) was added, then the mixture wasconcentrated. The title compound (717 mg) was obtained as a 3:1 mixtureof diastereomers by flash chromatography using 40% ethyl acetate inpetroleum ether as eluent.

¹ HNMR: consistent with structure.

HPLC: method A, Rt=13.48 min (major isomer)

TLC: R_(f) =0.5 (40% ethyl acetate in petroleum ether)

FABMS: M+1 at 525

Analysis calculated for C₂₈ H₃₆ N₄ O₄ S+0.3 ethyl acetate C, 63.93; H,7.02; N, 10.17 Found: C, 63.94; H, 7.09; N, 10.13

EXAMPLE 34 ##STR43##

To a solution of the product of Example 33 (40 mg, 0.08 mmol) in 9:1methanol:acetic acid (20 mL) was added zinc dust (10 eq). After stirringat room temperature for 4 h, the mixture was filtered and concentrated.The title compound (15 mg) was obtained through purification by flashchromatography (10% methanol in methylene chloride as eluent).

¹ HNMR: consistent with structure.

HPLC: method A, R_(t) =11.03

FABMS: M+1 at 527

Analysis calculated for C₂₈ H₃₈ N₄ O₄ S+0.5 water+0.25 hexanes C, 63.59;H, 7.69; N, 10.05 Found: C, 63.61; H, 7.31; N, 9.79

EXAMPLE 35 ##STR44##

To a solution of the product of Example 23 (1.03 g, 2 mmol) in drytetrahydrofuran(100 mL) was added diethylamino dibenzylphosphoramidite(1.78 g, 04 mmol), followed by tetrazole (280 mg, 4 mmol). After 2 h,the solution was cooled to -40° C., then m-chloroperbenzoic acid (1 g, 4mmol) in methylene chloride (12 mL) was added dropwise. The solution wasallowed to warm to 5° C. After 18 h, the mixture was partitioned betweenaqueous sodium bisulfite and methylene chloride. The methylene chloridelayer was dried over sodium sulfate, then concentrated. Flashchromatography (3% methanol in methylene chloride as eluent) allowed theseparation of two phosphorylated intermediates (mono anddiphosphorylated adducts) which were hydrogenated separately.

Each of the two phosphorylated intermediates was dissolved in ethanol.Palladium on carbon (10%) was added, then the mixtures were placed underhydrogen atmosphere. After 18 h, the mixtures were filtered andconcentrated. The product phosphates were purified by preparative HPLC.

mono phosphate:

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =11.27 min.

FABMS: M+1 at 597

Analysis calculated for C₂₇ H₃₇ N₂ O₉ S₁ P₁ +0.65 trifluoroaceticacid+0.70 dioxane C, 51.00; H, 5.95; N, 3.83 Found: C, 51.05; H, 6.35;N, 4.21

di phosphate:

¹ HNMR: consistent with structure.

HPLC: R_(t) =10.5 min.

FABMS: M+1 at 677

Analysis calculated for C₂₇ H₃₈ N₂ O₁₂ P₂ S₁ +1.50 dioxane C, 49.00; H,6.23; N, 3.46 Found: C, 48.97; H, 6.24; N, 3.43

EXAMPLE 36 ##STR45##

To a solution of endo- 1S!-1' 2-amino-7,7-dimethyl-bicyclo2.2.1!-hept-1yl!-methyl!-sulfonyl!spiro 1H-indan-1-4'-piperidine!(4 g,0.01 mol) in methylene chloride (20 mL) was added Boc-(D)-Aspartic acidbeta-benzyl ester (3.32 g, 0.012 mol), hydroxybenzotriazole (1.62 g,0.012 mol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.3 g, 0.012 mmol). After 18 hours the solution wasconcentrated, then partitioned between ethyl acetate and 1M NaOH (150 mLeach). The organic layer was washed with 1M HCl, and brine (150 mL each)then dried over Na₂ SO₄. The solution was filtered then concentrated.Purification by flash chromatography (40% ethyl acetate in petroleumether as eluent) gave an amide ester intermediate as white foam (3.7 g).

The foam (2.12 g, 0.003 mol) was dissolved in dry tetrahydrofuran (25mL) under nitrogen atmosphere, then cooled to -78° C. Lithiumhexamethyldisilylazide (7 mL, 1M solution in tetrahydrofuran) was addeddropwise. After 4 hours, a saturated solution of ammonium chloride wasadded, and the reaction mixture was allowed to warm to room temperature.The mixture was partitioned between ethyl acetate and water (150 mLeach). The ethyl acetate layer was dried 3.0 over sodium sulfate, thenconcentrated. Purification by flash chromatography (gradient from 15% to20% ethyl acetate in petroleum ether as eluent) afforded a protectedaminosuccinimide intermediate as a white foam.

To a solution of the Boc protected aminosuccinimide (2.7 g) in methylenechloride (10 mL) was added trifluoroacetic acid (5 mL). After 3 h, themixture was concentrated. Purification by flash chromatography (3%methanol in methylene chloride as eluent) afforded the title compound asa white foam (1.6 g).

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =11.96 min.

FABMS: M+1 at 500

Analysis calculated for C₂₇ H₃₇ N₃ O₄ S₁ +0.25 methylene chloride

C, 62.83; H, 7.26; N, 8.07 Found: C, 62.81; H, 7.19; N, 8.08

EXAMPLE 37 ##STR46##

To a solution of the product of Example 36 (24 mg, 0.05 mmol) inacetonitrile (1 mL) was added glycolic acid (9 mg, 0.06 mmol), followedby benzotriazolyl-N-oxy-tris(dimethylamino)phosonium hexafluorophosphate(26 mg, 0.06 mmol) and diisopropylethylamine (7.8 mg, 0.06 mmol). After18 h, the mixture was concentrated. The title compound was obtainedafter purification by preparative HPLC (17 mg).

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =14.46 min.

FABMS: M+1 at 558

Analysis calculated for C₂₉ H₃₉ N₃ O₆ S₁ +0.45 trifluoroacetic acid C,58.96; H, 6.53; N, 6.90 Found: C, 59.06; H, 6.72; N, 6.65

EXAMPLE 38 ##STR47##

To a solution of the product of Example 37 (200 mg, 0.36 mmol) in drytetrahydrofuran (15 mL) was added diethylamino dibenzylphosphoramidite(171 mg, 0.54 mmol), followed by tetrazole (75 mg, 1.08 mmol). After 18h at 9° C., the solution was cooled to -50° C., then m-chloroperbenzoicacid (139 mg) was added and the mixture was allowed to warm to roomtemperature. After 6 h, the mixture was concentrated, then partitionedbetween ethyl acetate and aqueous sodium bisulfite. The ethyl acetatewas dried over sodium sulfate, then concentrated. Preparative HPLCafforded the intermediate phosphorylated adduct.

The protected phosphate ester obtained above (100 mg) was dissolved inethanol (10 mL). To this solution was added 10% palladium on carbon (39mg), then the mixture was placed under a hydrogen atmosphere at 60 psi.After 18 h, the mixture was filtered then concentrated. Preparative HPLCafforded the title compound.

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =11.98 min.

FABMS: M+1 at 638

Analysis calculated for C₂₉ H₄₀ N₃ O₉ P₁ S₁ +1.5 water+0.6 dioxane C,52.55; H, 6.71; N, 5.86 Found: C, 52.53; H, 6.42; N, 5.84

EXAMPLE 39 ##STR48##

To a solution of the product of Example 29 (24 mg, 0.05 mmol) inmethylene chloride (0.5 mL) was added methanol (0.5 mL), followed byhistamine dihydrochloride (18 mg, 0.1 mmol) and diisopropylethylamine(26 mg, 0.2 mmol). After 18 h at room temperature the mixture wasconcentrated. The title compound was purified by preparative HPLC.

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =11.05 min.

FABMS: M+1 at 594

Analysis calculated for C₃₂ H₄₃ N₅ O₄ S₁ +2.40 trifluoroacetic acid C,50.96; H, 5.28; N, 8.07 Found: C, 50.92; H, 5.45; N, 8.14

EXAMPLE 40 ##STR49##

To a solution of the product of Example 29 (48 mg, 0.1 mmol) inmethylene chloride (2 mL) was added methanol (2 mL), followed bydimethylaminoethylamine (18 mg, 0.2 mmol). After 18 h at roomtemperature the mixture was concentrated. The title compound waspurified by preparative HPLC.

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =12.64 min.

FABMS: M+1 at 571

Analysis calculated for C₃₁ H₄₆ N₄ O₄ S₁ +0.55 water C, 64.11; H, 8.18;N, 9.65 Found: C, 64.07; H, 8.08; N, 9.49

EXAMPLE 41 ##STR50##

To a solution of the product of Example 29 (48 mg, 0.1 mmol) inmethylene chloride (0.5 mL) was added methanol (0.5 mL), followed bydimethylaminoethyl mercaptan hydrochloride (28 mg, 0.2 mmol) anddiisopropylethylamine (26 mg, 0.2 mmol). After 18 h at room temperaturethe mixture was concentrated. The title compound was purified bypreparative HPLC.

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =13.82 min.

FABMS: M+1 at 588

Analysis calculated for C₃₁ H₄₅ N₃ O₄ S₂ +1.3 TFA+0.05 dioxane C, 54.82;H, 6.36; N, 5.68 Found: C, 54.76; H, 6.37; N, 5.84

EXAMPLE 42 ##STR51##

To a solution of the product of Example 36 (25 mg, 0.05 mmol) inacetonitrile (5 mL) was added N-alpha-N-im-bis-Boc-L-Histidine (21 mg,0.06 mmol), followed by BOP reagent (26 mg, 0.06 mmol) anddiisopropylethylamine (7.8 mg, 0.06 mmol). After 18 h at roomtemperature the mixture was concentrated. Preparative HPLC afforded theBoc protected intermediate, which was dissolved in TFA (5 mL). After 2.5h, the mixture was concentrated. The title compound was purified bypreparative HPLC.

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =10.00 min.

FABMS: M+1 at 637

Analysis calculated for C₃₃ H₄₄ N₆ O₅ S₁ +2.20 TFA+1.75 water C, 48.87;H, 5.45; N, 9.14 Found: C, 48.86; H, 5.47; N, 8.96

EXAMPLE 43 ##STR52##

To a solution of the product of Example 36 (100 mg, 0.2 mmol) in DMF (10mL) was added N-alpha-Boc-L-arginine hydrochloride (75 mg, 0.24 mmol),followed by hydroxybenzotriazole (35 mg, 0.24 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.24mmol). After 18 h at room temperature the mixture was concentrated.Preparative HPLC afforded the Boc protected intermediate, which wasdissolved in 50% TFA in methylene chloride (6 mL). After 18 h, themixture was concentrated. The title compound (67 mg) was purified bypreparative HPLC.

¹ HNMR: consistent with structure.

HPLC: method B, R^(t) =9.80 min.

FABMS: M+1 at 656

Analysis calculated for C₃₃ H₄₉ N₅ O₅ S₁ +2.5 TFA+1.45 water C, 47.19;H, 5.67; N, 10.14 Found: C, 47.19; H, 5.62; N, 10.13

EXAMPLE 44 ##STR53##

To a solution of the product of Example 43 (approx. 0.4 mmol) inmethylene chloride (5 mL) was added diisopropylethylamine until the pHwas approximately 8.5. Acetyl chloride (31 mg) was added. After 18 h atroom temperature the mixture was concentrated. The title compound (138mg) was purified by preparative HPLC.

¹ HNMR: consistent with structure.

HPLC: method B, R_(t) =11.99 min.

FABMS: M+1 at 698

Analysis calculated for C35H51 N7O6S1+1.7 TFA+0.1 dioxane C, 51.74; H,5.99; N, 10.89 Found: C, 51.72; H, 6.13; N, 11.01

EXAMPLE 45

1-((7,7-Dimethyl-2-Oximino-Bicyclo(2.2.1)Heptan-1-yl)-Methane-sulfonyl)-4-(2-Methylphenyl)-3-Piperazine##STR54##

To a stirred solution of1-((7,7-dimethyl-2-oxo-bicyclo-(2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine(65.0 g; 166 mmol) in pyridine (250 mL) was added hydroxylaminehydrochloride (35.0 g; 0.504 mol). The solution was heated to 70° C. for18 h. The solvent was removed under reduced pressure, the residue wastaken up in chloroform (500 mL) and washed with aqueous NaHCO₃ (2×200mL), water (100 mL), and 5% aqueous HCl (2×200 mL). The organic phasewas dried (MgSO₄), filtered, and the solvent was removed under reducedpressure. The title compound crystallized from ethyl acetate, givingoff-white needles (57 g; 84%), mp 174°-175° C.

TLC: R_(f) 0.40 (7525 hexane-ethyl acetate)

HPLC (method A): retention time 9.98 min

FABMS: M+1 at 406

Analysis calculated for C₂₁ H₃₁ N₃ O₃ S C, 62.19; H, 7.71; N, 10.36Found: C, 62.29; H, 7.63; N, 10.15

¹ H NMR (300 MHz, CDCl₃): δ7.90 (br s, 1H), 7.18 (m, 2H), 7.02 (m, 2H),3.47 (m, 4H), 4.43 (d, J=14.4 Hz, 1H), 3.00 (m, 4H), 2.92 (d, J=14.4 Hz,1H), 2.4-2.6 (m, 2H), 2.31 (s, 3H), 2.09 (d, J=16.9 Hz, 1H), 1.95 (m,2H), 1.80 (m, 1H), 1.32 (m, 1H), 1.08 (s, 3H), 0.87 (s, 3H)

EXAMPLE 46

1-((7,7-Dimethyl-2-Endo-Amino-Bicyclo(2.2.1)Heptan-1-yl)Methane-sulfonyl)-4-(2-Methylphenyl)-3-Piperazine##STR55##

To a stirred solution of1-((7,7-dimethyl-2-oximino-bicyclo(2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine(35.0 g; 86 mmol) in 2-methoxyethanol (500 mL) containing Raney Nickelalloy (105.0 g) was added sodium hydroxide solution (17.2 g; 430 mmoldissolved in 75 mL) dropwise over 30 min. During the addition heat andgas was evolved. The mixture was stirred at ambient temperature for 16h, at which time TLC indicated complete consumption of starting oximeand a ca. 4:1 mixture of endo (lower R_(f)) and exo (higher R_(f)) amineproducts. The mixture was filtered through Celite and the filtercake waswashed with methanol and ethyl acetate. The solvents were removed underreduced pressure and the resulting solid was dispersed in water andfiltered. The dried solid was purified by pressurized silica gel columnchromatography, using a 93:3 to 94:6 A:B gradient elution (A=chloroform,B=5% NH₄ OH/MeOH). The title compound was obtained as a white foam (24g; 70%).

EXAMPLE 47 ##STR56##

The procedure of example 2 was carded out using the product of example46 1.38 mmol!, triethylamine 3.40 mmol!, and substituting glycine methylester hydrochloride 1.54 mmol! for histidine methyl esterdihydrochloride. The intermediate hydantoin was purified by flashchromatography using 5% methanol in methylene chloride as eluent.

To a stirred solution of the hydantoin (120 mg, 0.253 mmol) in drytetrahydrofuran (15 mL) was added 2R-(-)-glycidyl tosylate (288 mg, 1.26mmol), followed by sodium hydride (60% dispersion in oil). Thetemperature was increased to reflux. After 2 hours the mixture wascooled then concentrated. Purification by preparative TLC (40% ethylacetate in petroleum ether as eluent) afforded 1R-4-(2-methylphenyl)piperazin-1-yl)sulfonyl!-methyl!7,7-dimethylbicyclo2.2.1!hept-2-endo-yl!-3- 2S,3oxirane-1-propenyl!-2,5-dioxo-1-imidazolidine as a white foam (112 mg).

¹ HNMR: consistent with structure.

HPLC: method A; R_(t) =13.4 min; 98%

Analysis calculated for C₂₇ H₃₈ N₄ O₅ S+0.25 methylene chloride C,59.30; H, 7.03; N, 10.15 Found: C, 59.64; H, 7.10; N, 9.79

EXAMPLE 48 ##STR57##

To a solution of1-((7,7-dimethyl-2-endo-amino-bicyclo-(2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)-3-piperazine(103 mg, 0.286 mmol) in methylene chloride (15 mL) was added diacetyltartaric anhydride (71 mg, 0.315 mmol). After stirring for 1 h at roomtemperature, the mixture was concentrated, then dissolved in aceticanhydride (20 mL). Sodium acetate (47 mg, 0.572 mmol) was added, thenthe mixture was heated to 70° C. After 40 h, the mixture was cooled toroom temperature, then concentrated. Flash chromatography using 20%ethyl acetate in petroleum ether as eluent afforded 61 mg of the titlecompound as a white foam.

¹ HNMR: consistent with structure.

HPLC: method A; R_(t) =14.16 min; 98%

FABMS: M+1 at 590

Analysis calculated for C₂₉ H₃₉ N₃ O₈ S+0.15 hexanes+1.15 ethyl acetateC, 58.71; H, 7.15; N, 6.01 Found: C, 58.71; H, 6.91; N, 5.98

EXAMPLE 49 ##STR58##

To a solution of the product of Example 48 (20 mg, 0.033 mmol) in 3:1tetrahydrofuran:water (10 mL) at O° C. was added hydrogen peroxide (4eq), followed by lithium hydroxide (2 eq). After stirring at roomtemperature for 40 min, the mixture was concentrated. Flashchromatography using 10% methanol in methylene chloride as eluentafforded 14 mg of the title compound as a white foam.

¹ HNMR: consistent with structure.

HPLC: method A; R_(t) =11.4 min; 97%

FABMS: M+1 at 506

Analysis calculated for C₂₅ H₃₅ N₃ O₆ S+0.25 chloroform+0.20 water C,56.26; H, 6.67; N, 7.79 Found: C, 56.27; H, 6.55; N, 7.53

EXAMPLE 50 ##STR59##

The procedure of Example 36 was followed, where the product of example46 was used in place of endo- 1S!-1' 2-amino-7,7-dimethylbicyclo2.2.1!-hept-1yl!-methyl!-sulfonyl!spiro 1H-indan-1-4'-piperidine!, andBoc-(L)-Aspartic acid beta-methyl ester was used instead ofBoc-(D)-Aspartic acid beta-benzyl ester.

¹ HNMR: consistent with structure.

HPLC: method A; R_(t) =10.82 min; 98%

Analysis calculated for C₂₅ H₃₆ N₄ O₄ S+0.25 hexanes+0.50 methylenechloride. C, 58.68; H, 7.39; N, 10.14 Found: C, 58.73; H, 7.23; N, 10.22

EXAMPLE 51 ##STR60##

To a solution of the product of Example 50 (50 mg, 0.102 mmol) inmethylene chloride (15 mL) was added glycolic acid (12 mg, 0.15 mmol),followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(29 mg, 0.15 mmol) and 1-hydroxybenzotriazole (21 mg, 0.15 mmol). Afterstirring at room temperature for 18 h, the mixture was concentrated. Thetitle compound was purified by preparative HPLC.

¹ HNMR: consistent with structure.

TLC: R_(f) =0.4 (10% methanol in methylene chloride)

FABMS: M+1 at 547

Analysis calculated for C₂₇ H₃₇ N₄ O₆ S+0.95 trifluoroacetic acid C,53.08; H, 5.85; N, 8.57 Found: C, 52.97; H, 6.08; N, 8.17

                                      TABLE                                       __________________________________________________________________________    In addition to those compounds specifically exemplified above, additional     compounds of the present                                                      invention are set forth in tabular form below. These compounds are            synthesized by use of the synthetic                                           routes and methods described in the above Schemes and Examples and            variations thereof well known to                                              those of ordinary skill in the art, and not requiring undue                   experimentation. All variables listed in                                      the Tables below are with reference to the following generic structure:        ##STR61##                                                                    R                       R                                                     __________________________________________________________________________     ##STR62##                                                                                             ##STR63##                                                                     ##STR64##                                             ##STR65##                                                                                             ##STR66##                                             ##STR67##                                                                                             ##STR68##                                             ##STR69##                                                                                             ##STR70##                                             ##STR71##                                                                                             ##STR72##                                             ##STR73##                                                                     ##STR74##                                                                                             ##STR75##                                             ##STR76##                                                                     ##STR77##                                                                                             ##STR78##                                             ##STR79##                                                                                             ##STR80##                                             ##STR81##                                                                                             ##STR82##                                             ##STR83##                                                                                             ##STR84##                                             ##STR85##                                                                                             ##STR86##                                             ##STR87##                                                                                             ##STR88##                                             ##STR89##                                                                                             ##STR90##                                             ##STR91##                                                                                             ##STR92##                                             ##STR93##                                                                                             ##STR94##                                             ##STR95##                                                                                             ##STR96##                                             ##STR97##                                                                                             ##STR98##                                             ##STR99##                                                                                             ##STR100##                                            ##STR101##                                                                                            ##STR102##                                            ##STR103##                                                                                            ##STR104##                                            ##STR105##                                                                                            ##STR106##                                            ##STR107##                                                                                            ##STR108##                                            ##STR109##                                                                                            ##STR110##                                            ##STR111##                                                                                            ##STR112##                                            ##STR113##                                                                                            ##STR114##                                            ##STR115##                                                                                            ##STR116##                                            ##STR117##                                                                                            ##STR118##                                           __________________________________________________________________________

EXAMPLE 52 RADIOLIGAND BINDING ASSAYS

The high affinity binding of ³ H! Oxytocin (OT)( tyrosyl, 3,5- 3H!OT;30-60 Ci/mmol; New England Nuclear. Boston, Mass.) to uterine OTreceptors was based on an assay (Fuchs, A.-R; Fuchs, F.; Soloff, M. S.1985 J. Clin. Endocrinol. Metab. 6037) using a crude membranepreparation of uteri taken from diethylstilbestrol dipropionate(DES)-treated (0.3 mg/kg, ip; 18-24) rats. Competition studies wereconducted at equilibrium (60 minutes; 22° C.) using 1 nM ³ H!OT in thefollowing assay buffer 50 mM Tris-HCl, 5 mM MgCl₂, and 0.1% BSA, pH 7.4.Nonspecific binding (10% of the total binding) was determined using 1 μMunlabeled OT and the binding reaction was terminated by filtrationthrough glass fiber filters using a cell harvester (model 7019, Skatron,Inc., Sterling, Va.). IC₅₀ (the concentration of tested compound thatinhibits 50% of OT) was reported, unless otherwise noted.

The measurement of ³ H!Vasopressin (AVP) ( phenylalanyl-3,4,5-³ H!AVP;80-90 Ci/mmol; New England Nuclear) binding to a crude membranepreparation of male rat liver (AVP-V 1 sites) or kidney medulla (AVP-V2sites) was determined according to the method of Butlen, et al. (Butlen,D; Guillon, G; Rajerison, R. M.; Jard, S; Sawyer, W. H.; Manning, M.1978 Mol Pharmacol 14:1006).

Competition assays were conducted at equilibrium (30 minutes at 30° C.)using 1 nM ³ H!AVP (liver) or 2 nM ³ H!AVP (kidney) in the followingassay buffer 100 mM Tris-HCl, 5 mM MgCl₂, 0.1% BSA, 50 mMphenylmethylsulfonylfluoride, and 50 mg/ml bacitracin, pH 8.0.Nonspecific binding (5-10% of the total binding) was determined using 10μM unlabeled AVP, and the binding reaction was terminated by filtrationas described above for the ³ H!OT binding assay.

IC₅₀ values were determined for both ³ H!OT and ³ H!AVP binding assaysby linear regression of the relation log concentration of compound vs.percent inhibition of specific binding.

    ______________________________________                                        Example          Result For  .sup.3 H!OT                                      ______________________________________                                        29               70% inhib. @1000 nM                                          32               29 nM                                                        38               4.9 nM                                                       44               1.0 nM                                                       48               67 nM                                                        49               68 nM                                                        ______________________________________                                    

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forprevention of preterm labor, or for other indications for the compoundsof the invention indicated above. Likewise, the specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compound selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention. It is intended, therefore, that theinvention be limited only by the scope of the claims which follow andthat such claims be interpreted as broadly as is reasonable.

What is claimed is:
 1. A compound of the formula ##STR119## or apharmaceutically acceptable salt thereof, wherein X is ##STR120## a is asingle or double bond, R is Het, whereinHet is a substituted saturatedor unsaturated heterocyclic ring wherein said substituents areindependently one or more of R¹, R², R³, Alk-R¹, Alk-R², Alk-R³,--NHC(O)-Alk-R² R³, --NR⁵ -Alk-R² R³ or Alk-R² R³ ; where Alk is C₁₋₁₀alkyl and R¹, R² and R³ are independently selected from the groupconsisting of hydrogen, halogen, C₂₋₁₀ alkenyl, methylene, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkylamino, C₁₋₁₀alkoxycarbonylamino, C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl, C₁₋₁₀alkylcarbonylamino, --S--R⁴, C₁₋₁₀ alkylcarbonyloxy, C₁₋₁₀alkylsulfonyl, C₁₋₁₀ alkylthio, amino, amino C₁₋₁₀ alkylcarbonylamino,amino C₁₋₁₀ alkylamino, carbonylamino, carbamoyl, carboxyl C₁₋₁₀alkylamino, carboxyl, cyano, di-C₁₋₁₀ alkylamino, di-C₁₋₁₀alkylamino-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylthio,di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl, guanidinyl, hydroxyl,hydroxyl C₁₋₁₀ alkylamino, imidazolyl, imidazolyl amino, imidazolylC₁₋₁₀ alkylamino, imidazolyl C₁₋₁₀ alkylaminocarbonyl, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl,piperidinylamino, piperazinyl, pyrrolidinyl, sulfonyl, tetrazolyl C₁₋₁₀alkyl-carbonylamino, tetrazolylaminocarbonyl, phosphoryl, phosphorylC₁₋₁₀ alkylamino and thiono; R⁴ is selected from the group consisting ofimidazolyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkyl, di-C₁₋₁₀ alkylamino-C₁₋₁₀alkyl and C₁₋₅ alkyl; and R⁵ is selected from the group consisting ofhydrogen and C₁₋₅ alkyl.
 2. The compound as claimed in claim 1,whereinHet is a mono, di, tri or tetra substituted saturated orunsaturated 5 or 6 membered heterocyclic or 7 to 10 memberedheterobicyclic ring containing 1, 2 or 3 nitrogen atoms, and R¹, R² andR³ are independently selected from the group consisting of hydrogen,halogen, C₂₋₁₀ alkenyl, methylene, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀alkoxycarbonyl-C₁₋₁₀ alkylamino, C₁₋₁₀ alkylcarbonylamino, C₁₋₁₀alkylcarbonyloxy, C₁₋₁₀ alkylsulfonyl, --S--R⁴, amino, amino-C₁₋₁₀alkylcarbonylamino, amino C₁₋₁₀ alkylamino, carbamoyl, carboxyl C₁₋₁₀alkylamino, carboxyl, cyano, di-C₁₋₁₀ alkylamino, di-C₁₋₁₀alkylamino-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylthio,di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl, guanidinyl, hydroxyl,hydroxyl C₁₋₁₀ alkylamino, imidazolyl, imidazolyl amino, imidazolylC₁₋₁₀ alkylamino, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl,indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, sulfonyl,phosphoryl, phosphoryl C₁₋₁₀ alkylamino and thiono.
 3. The compound asclaimed in claim 2, wherein said bicyclic ring is bonded to one of saidheterocyclic or heterobicyclic ring's nitrogen atoms.
 4. The compound asclaimed in claim 3, whereinX is, ##STR121## and R¹, R² and R³ areindependently selected from the group consisting of hydrogen, halogen,C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀alkylamino, C₁₋₁₀ alkylcarbonylamino, C₁₋₁₀ alkylsulfonyl, --S--R⁴,amino, amino-C₁₋₁₀ alkylcarbonylamino, amino C₁₋₁₀ alkylamino,carbamoyl, carboxyl, cyano, di-C₁₋₁₀ alkylamino, di-C₁₋₁₀alkylamino-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylthio,guanidinyl, hydroxyl, hydroxyl C₁₋₁₀ alkylamino, imidazolyl, imidazolylamino, imidazolyl C₁₋₁₀ alkylamino, morpholinyl, thiomorpholinyl,dioxothiomorpholinyl, indolyl, oxo, phenyl, piperidinylamino,piperazinyl, sulfonyl, phosphoryl, phosphoryl C₁₋₁₀ alkylamino andthiono.
 5. The compound as claimed in claim 3, wherein Het is selectedfrom the group consisting of imidazolyl, imidazolinyl, imidazolidinyl,pyrrolyl, dihydropyrrolyl, pyrrolidinyl, piperazinyl, triazaspirodecane,pyrrolo-isoxazole, pyrrolo-pyrazole and pyrrolo-pyrrole.
 6. The compoundas claimed in claim 1, whereinX is ##STR122## R is Het, wherein Het is amono, di, tri or tetra substituted saturated or unsaturated 5 or 6membered heterocyclic ring containing 1, or 2 nitrogen atoms that isbonded to said bicyclic ring at one of said heterocyclic ring's nitrogenatoms, wherein said substituents are independently one or more of R¹,R², R³, Alk-R¹, Alk-R², Alk-R³ or Alk-R² R³ ; and where Alk is C₁₋₁₀alkyl and R¹, R² and R³ are independently selected from the groupconsisting of hydrogen, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀alkoxycarbonyl-C₁₋₁₀ alkylamino, C₁₋₁₀ alkoxycarbonylamino, C₁₋₁₀alkylamino-C₁₋₁₀ alkylaminocarbonyl, C₁₋₁₀ alkylcarbonylamino, C₁₋₁₀alkylcarbonyloxy, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ alkylthio, amino,amino-C₁₋₁₀ alkylcarbonylamino, carbonylamino, carboxyl C₁₋₁₀alkylamino, carboxyl, cyano, di-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylaminoC₁₋₁₀ alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl, imidazolylC₁₋₁₀ alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino,piperizinyl, pyrrolidinyl, sulfonyl, tetrazolyl C₁₋₁₀alkylcarbonylamino, tetrazolylaminocarbonyl and thiono.
 7. The compoundas claimed in claim 6, wherein a is a single bond, and R¹, R² and R³ areindependently selected from the group consisting of hydrogen, C₂₋₁₀alkenyl, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkylamino,C₁₋₁₀ alkylcarbonylamino, C₁₋₁₀ alkylcarbonyloxy, C₁₋₁₀ alkylsulfonyl,amino, amino-C₁₋₁₀ alkylcarbonylamino, carbonylamino, carboxyl, cyano,di-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylaminocarbonyl,guanidinyl, hydroxyl, imidazolyl, imidazolyl C₁₋₁₀ alkylaminocarbonyl,indolyl, oxo, phenyl, piperidinylamino, piperazinyl, sulfonyl andthiono.
 8. The compound as claimed in claim 7, wherein Het is selectedfrom the group consisting of imidazolyl, imidazolinyl, imidazolidinyl,pyrrolyl, dihydropyrrolyl, pyrrolidinyl and piperazinyl.
 9. The compoundas claimed in claim 2, whereinX is ##STR123## and R¹, R² and R³ areindependently selected from the group consisting of hydrogen, halogen,C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀alkylamino, C₁₋₁₀ alkylcarbonylamino, C₁₋₁₀ alkylcarbonyloxy, C₁₋₁₀alkylsulfonyl, --S--R⁴, amino, amino-C₁₋₁₀ alkylcarbonylamino, aminoC₁₋₁₀ alkylamino, carbamoyl, carboxyl, cyano, di-C₁₋₁₀ alkylamino,di-C₁₋₁₀ alkylamino-C₁₋₁₀ alkylamino, di-C₁₋₁₀ alkylamino-C₁₋₁₀alkylthio, guanidinyl, hydroxyl, hydroxyl C₁₋₁₀ alkylamino, imidazolyl,imidazolyl amino, imidazolyl C₁₋₁₀ alkylamino, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl,piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C₁₋₁₀alkylamino and thiono.
 10. The compound as claimed in claim 9, whereinR¹, R² and R³ are independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkylcarbonyloxy, amino, hydroxyl, oxo, phosphoryl andoxiranyl.
 11. The compound as claimed in claim 5, selected from thegroup consisting of ##STR124##
 12. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a pharmacologicallyeffective amount of the compound as claimed in claim 1, sufficient toantagonize oxytocin from binding to its receptor site.
 13. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a pharmacologically effective amount of the compound asclaimed in claim 1 sufficient to prevent preterm labor in a mammal inneed thereof.
 14. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a pharmacologically effectiveamount of the compound as claimed in claim 1, sufficient to stop laborpreparatory to cesarian delivery.
 15. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a pharmacologicallyeffective amount of the compound as claimed in claim 1, sufficient totreat dysmenorrhea.
 16. A compound of the formula ##STR125## or apharmaceutically acceptable salt thereof, wherein X is ##STR126## a andb represent a single or double bond, R is selected from the groupconsisting of ##STR127## R² is selected from the group consisting of-AlkR⁵ R⁶, --NH--C(O)-Alk-R⁷ R⁸, --N(R⁴)-Alk-R⁷ R⁸, amino C₁₋₁₀alkylcarbonylamino, piperidinylamino, oxiranyl C₁₋₁₀ alkyl,imidazolylamino, C₁₋₁₀ alkoxycarbonyloxy, hydroxyl, phosphoryl, --S--R⁹,C₁₋₁₀ alkylcarbonyloxy and C₁₋₁₀ alkylcarbonylamino; Alk is C₁₋₁₀alkyl;R³ is selected from the group consisting of hydrogen, hydroxyl,phosphoryl, C₁₋₁₀ alkylcarbonyloxy and C₁₋₁₀ alkoxycarbonyl; R⁴ isselected from the group consisting of hydrogen, benzyl and C₁₋₁₀ alkyl;R⁵ and R⁶ are independently selected from the group consisting ofhydroxyl, di-C₁₋₁₀ alkylamino, piperazinyl, halogen, phosphoryl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hydroxyl C₁₋₁₀alkylamino, cyano and --SCH₃ ; R⁷ and R⁸ are independently selected fromthe group consisting of hydrogen, hydroxyl, hydroxyl C₁₋₁₀ alkyl, C₁₋₁₀alkylcarbonylamino, amino, phosphoryl, imidazolyl, di-C₁₋₁₀ alkylamino,guanidinyl, C₁₋₁₀ alkoxycarbonyl, carboxyl and C₁₋₁₀alkoxycarbonylamino; R⁹ is selected from the group consisting ofdi-C₁₋₁₀ alkylamino-C₁₋₁₀ alkyl, imidazolyl and C₁₋₁₀alkoxycarbonyl-C₁₋₁₀ alkyl; provided that R⁵ and R⁶ cannot both behydroxyl.